Search

Sorbents designed for direct air capture (DAC) play a crucial role in the pursuit of achieving net-zero carbon dioxide emissions. This study elucidates CO2 adsorption from dilute, humidified CO2 streams onto an amine-modified benchmark DAC adsorbent via solid-state NMR spectroscopy. Various NMR techniques, including 1D 1H MAS, 13C MAS, 2D 1H-13C HETCOR NMR, and 1H R2 and R1ρ relaxometry reveal the impact of CO2 partial pressure and H2O on CO2 adsorption behavior. We find that CO2 concentration governs the stepwise formation of ammonium carbamate, carbamic acid, and physisorbed CO2, where relative humidity (RH) at a desired low (

Abstract Background Young adult suicidality is worldwide a prevalent mental health problem and the number one cause of death, with devastating consequences for individuals and their families, and substantial economic costs. However, psychological and pharmacological treatments currently recommended in guidelines for treatment of high-risk youth for fatal suicide have limited effect. In line with the World Health Organization’s (WHO) recommendation to involve the family in treatment of these youth, attachment-based family therapy (ABFT) was developed, a 16-week attachment and emotion-focused treatment, implemented in mental health care settings across various European countries in the past years, and becoming increasingly popular among therapists. However, the (cost-)effectiveness of ABFT has not been studied in emerging adults. In the proposed pragmatic randomized controlled trial (RCT), we aim to evaluate the effectiveness and cost-effectiveness of ABFT compared to treatment as usual (TAU) on suicidality, as delivered in daily practice. Methods This pragmatic multicenter study in the Netherlands and Belgium includes 13 participating sites. Participants are suicidal young adults (≥ 31 SIQ-JR score) between 16 and 30 years old who seek mental health treatment (n = 142) and their caregivers. The primary outcome is suicidality (SIQ-JR), with assessments at baseline, post-intervention (5 months after baseline), 3, 6, and 12 months after intervention. We predict that, compared to TAU, ABFT will lead to a stronger reduction in suicidality and will be more cost-effective, over the course of all time points. We also expect stronger decreases in depressive symptoms, given that suicidality is very common in individuals with depressive disorder, as well as more improvement in family functioning, autonomy, entrapment, and young adult attachment, in the ABFT condition. Discussion This study can contribute to improving the care for suicidal youngsters with high mortality risk. Treatment of suicidal emerging adults is understudied. The results will inform clinical guidelines and policy makers and improve treatment of suicidal emerging adults. Trial registration This trial is registered on ClinicalTrials.gov (NCT05965622, first posted on July 28, 2023).

Abstract Background Timor-Leste’s food insecurity, propelled by political conflicts, a fragile economy and biophysical limitations that characterize mountainous Small Island Developing States (SIDS), is expressed in a high incidence (50%) of stunted children. Hence, the Millennium Development Goals Achievement Fund’s Joint Program’s (MDG-F JP) in 2009 was a timely intervention to reduce prevalence of underweight among under-fives. Since the impact of the program remains largely unclear, the current study investigates the contributions of the MDG-F JP on improving children’s nutritional status in Timor-Leste, in order to inform policymakers on how to make future programs more effective. Methods Using bivariate analyses and multiple linear regression models we analyzed Demographic and Health Survey (DHS) data from under-fives in 2009–2010 and 2016, combined with spatially explicit data from geographic information systems (GIS). The analyses generated trends and factors associated with undernutrition, which were used in a quasi-experimental setting to compare districts that received the MDG-F JP with similar districts that did not receive MDG-F JP interventions. Results A comprehensive set of factors dependent on seasons, locations, and individuals determine undernutrition in Timor-Leste. A positive impact of the MDG-F JP was found for the average severity of wasting, but not for stunting and underweight. Conclusions The findings reinforce the pressing need for integrated and cross-sectoral programs, aimed especially at agricultural workers, mothers, and children. The agricultural challenge is to sustainably select, produce and conserve higher-yield and nutrient-rich crops, and educational enhancement should be aligned with local practices and research.

IntroductionPediatric patients with unexplained bone marrow failure (BMF) are often categorized as aplastic anemia (AA). Based on the accepted hypothesis of an auto-immune mechanism underlying AA, immune suppressive therapy (IST) might be effective. However, due to the lack of diagnostic tools to identify immune AA and prognostic markers to predict IST response together with the unequaled curative potential of hematopoietic stem cell transplantation (HSCT), most pediatric severe AA patients are momentarily treated by HSCT if available. Although several studies indicate oligoclonal T-cells with cytotoxic activities towards the hematopoietic stem cells, increasing evidence points towards defective inhibitory mechanisms failing to inhibit auto-reactive T-cells.MethodsWe aimed to investigate the role of NK- and B-cells in seven pediatric AA patients through a comprehensive analysis of paired bone marrow and peripheral blood samples with spectral flow cytometry in comparison to healthy age-matched bone marrow donors. ResultsWe observed a reduced absolute number of NK-cells in peripheral blood of AA patients with a skewed distribution towards CD56bright NK-cells in a subgroup of patients. The enriched CD56bright NK-cells had a lower expression of CD45RA and TIGIT and a higher expression of CD16, compared to healthy donors. Functional analysis revealed no differences in degranulation. However, IFN-γ production and perforin expression of NK-cells were reduced in the CD56bright-enriched patient group. The diminished NK-cell function in this subgroup might underly the auto-immunity. Importantly, NK-function of AA patients with reduced CD56bright NK-cells was comparable to healthy donors. Also, B-cell counts were lower in AA patients. Subset analysis revealed a trend towards reduction of transitional B-cells in both absolute and relative numbers compared to healthy controls. As these cells were previously hypothesized as regulatory cells in AA, decreased numbers might be involved in defective inhibition of auto-reactive T-cells. Interestingly, even in patients with normal distribution of precursor B-cells, the transitional compartment was reduced, indicating partial differentiation failure from immature to transitional B-cells or a selective loss. DiscussionOur findings provide a base for future studies to unravel the role of transitional B-cells and CD56bright NK-cells in larger cohorts of pediatric AA patients as diagnostic markers for immune AA and targets for therapeutic interventions.

IntroductionSarcoidosis is a multi-system inflammatory disease of unknown origin with heterogeneous clinical manifestations varying from a single organ non-caseating granuloma site to chronic systemic inflammation and fibrosis. Gene expression studies have suggested several genes and pathways implicated in the pathogenesis of sarcoidosis, however, due to differences in study design and variable statistical approaches, results were frequently not reproducible or concordant. Therefore, meta-analysis of sarcoidosis gene-expression datasets is of great importance to robustly establish differentially expressed genes and signalling pathways.MethodsWe performed meta-analysis on 22 published gene-expression studies on sarcoidosis. Datasets were analysed systematically using same statistical cut-offs. Differentially expressed genes were identified by pooling of p-values using Edgington’s method and analysed for pathways using Ingenuity Pathway Analysis software.ResultsA consistent and significant signature of novel and well-known genes was identified, those collectively implicated both type I and type II interferon mediated signalling pathways in sarcoidosis. In silico functional analysis showed consistent downregulation of eukaryotic initiation factor 2 signalling, whereas cytokines like interferons and transcription factor STAT1 were upregulated. Furthermore, we analysed affected tissues to detect differentially expressed genes likely to be involved in granuloma biology. This revealed that matrix metallopeptidase 12 was exclusively upregulated in affected tissues, suggesting a crucial role in disease pathogenesis.DiscussionOur analysis provides a concise gene signature in sarcoidosis and expands our knowledge about the pathogenesis. Our results are of importance to improve current diagnostic approaches and monitoring strategies as well as in the development of targeted therapeutics.

This paper discusses best practices for sharing and reusing Ground Truth in Handwritten Text Recognition infrastructures, as well as ways to reference and acknowledge contributions to the creation and enrichment of data within these systems. We discuss how one can place Ground Truth data in a repository and, subsequently, inform others through HTR-United. Furthermore, we want to suggest appropriate citation methods for ATR data, models, and contributions made by volunteers. Moreover, when using digitised sources (digital facsimiles), it becomes increasingly important to distinguish between the physical object and the digital collection. These topics all relate to the proper acknowledgement of labour put into digitising, transcribing, and sharing Ground Truth HTR data. This also points to broader issues surrounding the use of machine learning in archival and library contexts, and how the community should begin to acknowledge and record both contributions and data provenance.

Abstract Nonlinear damping, the change in damping rate with the amplitude of oscillations plays an important role in many electrical, mechanical and even biological oscillators. In novel technologies such as carbon nanotubes, graphene membranes or superconducting resonators, the origin of nonlinear damping is sometimes unclear. This presents a problem, as the damping rate is a key figure of merit in the application of these systems to extremely precise sensors or quantum computers. Through measurements of a superconducting resonator, we show that from the interplay of quantum fluctuations and the nonlinearity of a Josephson junction emerges a power-dependence in the resonator response which closely resembles nonlinear damping. The phenomenon can be understood and visualized through the flow of quasi-probability in phase space where it reveals itself as dephasing. Crucially, the effect is not restricted to superconducting circuits: we expect that quantum fluctuations or other sources of noise give rise to apparent nonlinear damping in systems with a similar conservative nonlinearity, such as nano-mechanical oscillators or even macroscopic systems.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

One of the main questions regarding Dutch primary education in our secularised and religiously diverse society--both with regards to public and religiously-affiliated schools--is how to get students acquainted with the symbolic language of religious and worldview-affiliated life narratives. Teaching literacy in symbolic language has become less important in the education programmes of modern-day primary schools. The dominance of scientific descriptive language is evident in the majority of contemporary curricula. This language may be highly important for teaching mathematics and science, but for religious and cultural education, and for teaching art and history, symbolic language is the vehicle for acquiring knowledge, insight, and wisdom. Our aim in this article is to reflect on the idea that stimulating symbolic speech in primary school education through role playing, will bring out the sensitivity of current-day students to confer meaning to life questions and life themes.

Abstract Background This Phase 1 study evaluates the intra- and peritumoral administration by convection enhanced delivery (CED) of human recombinant Bone Morphogenetic Protein 4 (hrBMP4) – an inhibitory regulator of cancer stem cells (CSCs) – in recurrent glioblastoma. Methods In a 3 + 3 dose escalation design, over four to six days, fifteen recurrent glioblastoma patients received, by CED, one of five doses of hrBMP4 ranging from 0·5 to 18 mg. Patients were followed by periodic physical, neurological, blood testing, magnetic resonance imaging (MRI) and quality of life evaluations. The primary objective of this first-in-human study was to determine the safety, dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of hrBMP4. Secondary objectives were to assess potential efficacy and systemic exposure to hrBMP4 upon intracerebral infusion. Results Intra- and peritumoral infusion of hrBMP4 was safe and well-tolerated. We observed no serious adverse events related to this drug. Neither MTD nor DLT were reached. Three patients had increased hrBMP4 serum levels at the end of infusion, which normalized within 4 weeks, without sign of toxicity. One patient showed partial response and two patients a complete (local) tumor response, which was maintained until the most recent follow-up, 57 and 30 months post-hrBMP4. Tumor growth was inhibited in areas permeated by hrBMP4. Conclusion Local delivery of hrBMP4 in and around recurring glioblastoma is safe and well-tolerated. Three patients responded to the treatment. A complete response and long-term survival occurred in two of them. This warrants further clinical studies on this novel treatment targeting glioblastoma CSCs. Trial registration : ClinicaTrials.gov identifier: NCT02869243.

We present a patient at risk of misdiagnosis with multiple myeloma due to pseudohypercalcemia. Examinations showed monoclonal protein, 50% monoclonal plasma cells in bone marrow, and hypercalcemia but no osteolytic bone lesions. Follow-up tests revealed pseudohypercalcemia, with elevated total calcium, but normal ionized calcium: a discrepancy due to calcium binding to monoclonal paraprotein (confirmed by laboratory experiments). Accordingly, the patient was diagnosed with smouldering myeloma. After 900 days, the presence of bone lesions prompted the start of treatment for myeloma. Consequently, monoclonal paraprotein levels declined and pseudohypercalcemia dissolved. Hence, ionized calcium should be measured in monoclonal gammopathies to avoid misdiagnosis.

IntroductionSchistosomiasis is a parasitic disease in Tanzania affecting over 50% of the population. Current control strategies involve mass drug administration (MDA) campaigns at the district level, which have led to problems of over- and under-treatment in different areas. WHO guidelines have called for more targeted MDA to circumvent these problems, however a scarcity of prevalence data inhibits decision makers from prioritizing sub-district areas for MDA. This study demonstrated how geostatistics can be used to inform planning for targeted MDA.MethodsGeostatistical sub-district (ward-level) prevalence estimates were generated through combining a zero-inflated poisson model and kriging approach (regression kriging). To make predictions, the model used prevalence survey data collected in 2021 of 17,400 school children in six regions of Tanzania, along with several open source ecological and socio-demographic variables with known associations with schistosomiasis.ResultsThe model results show that regression kriging can be used to effectively predict the ward level parasite prevalence of the two species of Schistosoma endemic to the study area. Kriging was found to further improve the regression model fit, with an adjusted R-squared value of 0.51 and 0.32 for intestinal and urogenital schistosomiasis, respectively. Targeted treatment based on model predictions would represent a shift in treatment away from 193 wards estimated to be over-treated to 149 wards that would have been omitted from the district level MDA.ConclusionsGeostatistical models can help to support NTD program efficiency and reduce disease transmission by facilitating WHO recommended targeted MDA treatment through provision of prevalence estimates where data is scarce.

Abstract Background End-stage renal disease (ESRD) patients treated with renal replacement therapy (RRT) have premature immunologically aged T cells which may underlie uremia-associated immune dysfunction. The aim of this study was to investigate whether uremia was able to induce premature ageing of the T cell compartment. For this purpose, we examined the degree of premature immunological T cell ageing by examining the T cell differentiation status, thymic output via T cell receptor excision circle (TREC) content and proliferative history via relative telomere length in ESRD patients not on RRT. Results Compared to healthy controls, these patients already had a lower TREC content and an increased T cell differentiation accompanied by shorter telomeres. RRT was able to enhance CD8+ T cell differentiation and to reduce CD8+ T cell telomere length in young dialysis patients. An increased differentiation status of memory CD4+ T cells was also noted in young dialysis patients. Conclusion Based on these results we can conclude that uremia already causes premature immunological ageing of the T cell system and RRT further increases immunological ageing of the CD8+ T cell compartment in particular in young ESRD patients.

Purpose: Very preterm (VPT) children are at risk for speech and language problems throughout school age. However, little is known about early speech sound production in these children. This study aims to present a detailed description of early speech sound production and its trajectories in VPT children from 2 to 4 years of age. In addition, this study aimed to determine if early speech sound production is associated with speech production and expressive language function at 4 years of age. Method: In 63 VPT children (< 32 weeks of gestation, 41 boys, mean gestational age = 28.8 weeks, mean birth weight = 1,135 g), speech sound production was assessed by naturalistic speech analysis at 2 years of corrected age and speech and language function by standardized tests at 4 years of age. Results: Speech sound production was found to be abnormal in 49% of the VPT children at 2 years of age and in 19% at 4 years of age. Four different speech production trajectories from 2 to 4 years of age could be identified: a normal trajectory, an abnormal trajectory, a catch-up trajectory, and a growing-into-deficit trajectory. Early speech production, defined by the number of acquired consonants at 2 years of age, significantly predicted the word production score at 4 years of age and the sentence production score at 4 years of age. Conclusions: Compared to the general population, an alarmingly high proportion of VPT children showed speech production problems at 2 years of age. About half of these children showed persistent speech problems at 4 years of age. Moreover, these problems were associated with expressive language problems at the age of 4 years.

Abstract Background Older individuals are often underrepresented in clinical trials. In 2012 only 7% of RCT’s specifically studied older people and their geriatric characteristics were poorly reported. The aim of this review was to investigate temporal changes in characteristics and external validity of randomized controlled trials in older people from 2012 to 2019. Methods PubMed was searched for randomized clinical trials (RCTs) published in 2019. Firstly, the proportion of RCTs specially designed for older people were determined by the following criteria: a reported mean age of ≥ 70 years or a lower age cutoff of ≥ 55. Secondly, the trials with a majority of older people, defined by a reported mean age of ≥ 60 years, were screened for reporting of geriatric assessments. Both parts were compared with identical reviews performed in 2012. Results From a 10% random sample, 1446 RCTs were included in this systematic review. First, 8% of trials were specifically designed for older people in 2019 compared to 7% in 2012. Secondly, 25% of the trials included a majority of older people in 2019, compared to 22% in 2012. Thirdly, in 52% of these trials in 2019 one or more of the geriatric assessments were reported compared to 34% in 2012. Conclusions Although in 2019 the proportion of published RCTs specifically designed for older people remains low, more characteristics on geriatric assessments were reported compared to 2012. Continued efforts should be paid to increase both the number and the validity of trials for older people.

Abstract Background Studies focusing on sex differences in circulating proteins in patients with heart failure with reduced ejection fraction (HFrEF) are scarce. Insight into sex-specific cardiovascular protein profiles and their associations with the risk of adverse outcomes may contribute to a better understanding of the pathophysiological processes involved in HFrEF. Moreover, it could provide a basis for the use of circulating protein measurements for prognostication in women and men, wherein the most relevant protein measurements are applied in each of the sexes. Methods In 382 patients with HFrEF, we performed tri-monthly blood sampling (median follow-up: 25 [13–31] months). We selected all baseline samples and two samples closest to the primary endpoint (PEP: composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization) or censoring. We then applied an aptamer-based multiplex proteomic assay identifying 1105 proteins previously associated with cardiovascular disease. We used linear regression models and gene-enrichment analysis to study sex-based differences in baseline levels. We used time-dependent Cox models to study differences in the prognostic value of serially measured proteins. All models were adjusted for the MAGGIC HF mortality risk score and p-values for multiple testing. Results In 104 women and 278 men (mean age 62 and 64 years, respectively) cumulative PEP incidence at 30 months was 25% and 35%, respectively. At baseline, 55 (5%) out of the 1105 proteins were significantly different between women and men. The female protein profile was most strongly associated with extracellular matrix organization, while the male profile was dominated by regulation of cell death. The association of endothelin-1 (Pinteraction

Abstract Synapse diversity has been described from different perspectives, ranging from the specific neurotransmitters released, to their diverse biophysical properties and proteome profiles. However, synapse diversity at the transcriptional level has not been systematically identified across all synapse populations in the brain. To quantify and identify specific synaptic features of neuronal cell types we combined the SynGO (Synaptic Gene Ontology) database with single-cell RNA sequencing data of the mouse neocortex. We show that cell types can be discriminated by synaptic genes alone with the same power as all genes. The cell type discriminatory power is not equally distributed across synaptic genes as we could identify functional categories and synaptic compartments with greater cell type specific expression. Synaptic genes, and specific SynGO categories, belonged to three different types of gene modules: gradient expression over all cell types, gradient expression in selected cell types and cell class- or type-specific profiles. This data provides a deeper understanding of synapse diversity in the neocortex and identifies potential markers to selectively identify synapses from specific neuronal populations.

Thyroid hormones play an essential role in regulating whole-body homeostasis. Deiodinases are known to convert thyroid hormone from the prohormone thyroxine (T4) to the bioactive hormone tri-iodothyronine (T3) and convert both T4 and T3 toward their inactive metabolites 3,3’,5’-tri-iodothyronine (rT3) and 3,3’-di-iodothyronine (3,3’- T2). Deiodinases are thus important for the regulation of intracellular thyroid hormone concentrations. This is known to be crucial both during development and adult life in regulating thyroid hormone-related gene transcription. This review discusses the importance of liver deiodinases in determining serum and liver thyroid hormone concentrations, liver metabolism and liver disease.

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.