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Summary: Forest soils play a pivotal role as global carbon (C) sinks, where the dynamics of soil organic matter (SOM) are significantly influenced by ectomycorrhizal (ECM) fungi. While correlations between ECM fungal community composition and soil C storage have been documented, the underlying mechanisms behind this remain unclear.Here, we conducted controlled experiments using pure cultures growing on naturally complex SOM extracts to test how ECM fungi regulate soil C and nitrogen (N) dynamics in response to varying inorganic N availability, in both monoculture and mixed culture conditions.ECM species dominant in N‐poor soils exhibited superior SOM decay capabilities compared with those prevalent in N‐rich soils. Inorganic N addition alleviated N limitation for ECM species but exacerbated their C limitation, reflected by reduced N compound decomposition and increased C compound decomposition. In mixed cultures without inorganic N supplementation, ECM species with greater SOM decomposition potential facilitated the persistence of less proficient SOM decomposers. Regardless of inorganic N availability, ECM species in mixed cultures demonstrated a preference for C over N, intensifying relatively labile C compound decomposition.This study highlights the complex interactions between ECM species, their nutritional requirements, the nutritional environment of their habitat, and their role in modifying SOM. [ABSTRACT FROM AUTHOR]

Background: To describe the societal costs during one year of follow-up among older adults seeking chiropractic care due to a new episode of low back pain (LBP), and to determine what factors predict high societal costs in this population. Methods: Prospective cohort study, within chiropractic private practices (n = 38) in the Netherlands. 223 people ≥ 55 years of age with a new episode of LBP seeking chiropractic care participated. The primary outcome was total societal costs. High societal costs were defined as patients with costs in the top 20th percentile. The final prediction models were obtained using forward selection. Results were presented for the total population and stratified for retirement status. The model's prognostic accuracy (Hosmer–Lemeshow X2, Nagelkerke's R2) and discriminative ability [area under the receiver operating curve (AUC)] were assessed, and the models were internally validated using bootstrapping. Results: The mean total annual societal cost per patient was €5297 [95% confidence interval (CI): 4191–6403]. The biggest cost driver was presenteeism (65% of total costs), and costs were higher among non-retired participants (€7759; 95% CI 6047–9470) than retired participants (€1892; 95% CI 1088–2695). In the total population, younger age [odds ratio (OR): 0.87 for each additional year; 95% CI 0.80–0.95], being male instead of female (OR 2.96; 95% CI 1.19–7.44), less alcohol intake (OR 0.49; 95% CI 0.20–1.19), working instead of retirement (OR 9.37; 95% CI 1.83–48.04), and more disability at baseline (OR 1.08; 95% CI 1.00–1.16) were found to be predictive of high societal costs. Working was found to be the strongest predictor for high societal costs. After internal validation, the model's fit was good, it's explained variance was moderate (28%) and their AUCs could be interpreted as moderate (0.85). For non-pensioners, the same predictive factors were identified as for the entire population. The costs for the retired participants showed too little variation to be able to predict high costs. Conclusions: This study estimated the mean total annual societal cost of older adults seeking chiropractic care due to a new episode of LBP at €5297 (95% CI 4191–6403).These costs were mainly due to high levels of presenteeism, and extensively differed based upon work status. [ABSTRACT FROM AUTHOR]

Background: Asthma, a complex respiratory disease, presents with inflammatory symptoms in the lungs, blood, and other tissues. We investigated the relationship between DNA methylation and 35 clinical markers of asthma. Methods: The Illumina Infinium EPIC v1 methylation array was used to evaluate 742,442 CpGs in whole blood from 319 participants from 94 families. They were part of the Netherlands Twin Register from families with at least one member suffering from severe asthma. Repeat blood samples were taken after 10 years from 182 individuals. Principal component analysis on the clinical asthma markers yielded ten principal components (PCs) that explained 92.8% of the total variance. We performed epigenome-wide association studies (EWAS) for each of the ten PCs correcting for familial structure and other covariates. Results: 221 unique CpGs reached genome-wide significance at timepoint 1 after Bonferroni correction. PC7, which correlated with loadings of eosinophil counts and immunoglobulin levels, accounted for the majority of associations (204). Enrichment analysis via the EWAS Atlas identified 190 of these CpGs to be previously identified in EWASs of asthma and asthma-related traits. Proximity assessment to previously identified SNPs associated with asthma identified 17 unique SNPs within 1 MB of two of the 221 CpGs. EWAS in 182 individuals with epigenetic data at a second timepoint identified 49 significant CpGs. EWAS Atlas enrichment analysis indicated that 4 of the 49 were previously associated with asthma or asthma-related traits. Comparing the estimates of all the significant associations identified across the two time points yielded a correlation of 0.81. Conclusion: We identified 270 unique CpGs that were associated with PC scores generated from 35 clinical markers of asthma, either cross-sectionally or 10 years later. A strong correlation was present between effect sizes at the 2 timepoints. Most associations were identified for PC7, which captured blood eosinophil counts and immunoglobulin levels and many of these CpGs have previous associations in earlier studies of asthma and asthma-related traits. The results point to a robust DNA methylation profile as a new, stable biomarker for asthma. [ABSTRACT FROM AUTHOR]

The stromal vascular fraction of adipose tissue has gained popularity as regenerative therapy for tissue repair. Both enzymatic and mechanical intraoperative SVF isolation procedures exist. To date, the quest for the preferred isolation procedure persists, due to the absence of standardised yield measurements and a defined clinical threshold. This systematic review is an update of the systematic review published in 2018, where guidelines were proposed to improve and standardise SVF isolation procedures. An elaborate data search in MEDLINE (PubMed), EMBASE (Ovid) and the Cochrane Central Register of Controlled Trials was conducted from September 2016 to date. A total of 26 full‐text articles met inclusion criteria, evaluating 33 isolation procedures (11 enzymatic and 22 mechanical). In general, enzymatic and mechanical SVF isolation procedures yield comparable outcomes concerning cell yield (2.3–18.0 × 105 resp. 0.03–26.7 × 105 cells/ml), and cell viability (70%–99% resp. 46%–97.5%), while mechanical procedures are less time consuming (8–20 min vs. 50–210 min) and cost‐efficient. However, as most studies used poorly validated outcome measures on SVF characterisation, it still remains unclear which intraoperative SVF isolation method is preferred. Future studies are recommended to implement standardised guidelines to standardise methods and improve comparability between studies. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Besides neurofibrillary tangles and amyloid beta (Aβ) plaques, a wide range of co-morbid neuropathological features can be observed in AD brains. Since AD has a very strong genetic background and displays a wide phenotypic heterogeneity, this study aims at investigating the genetic underpinnings of co-morbid and hallmark neuropathological lesions. This was realized by obtaining the genotypes for 75 AD risk variants from low-coverage whole-genome sequencing data for 325 individuals from the Leuven Brain Collection. Association testing with deeply characterized neuropathological lesions revealed a strong and likely direct effect of rs117618017, a SNP in exon 1 of APH1B, with tau-related pathology. Second, a relation between APOE and granulovacuolar degeneration, a proxy for necroptosis, was also discovered in addition to replication of the well-known association of APOE with AD hallmark neuropathological lesions. Additionally, several nominal associations with AD risk genes were detected for pTDP pathology, α-synuclein lesions and pTau-related pathology. These findings were confirmed in a meta-analysis with three independent cohorts. For example, we replicated a prior association between TPCN1 (rs6489896) and LATE-NC risk. Furthermore, we identified new putative LATE-NC-linked SNPs, including rs7068231, located upstream of ANK3. We found association between BIN1 (rs6733839) and α-synuclein pathology, and replicated a prior association between USP6NL (rs7912495) and Lewy body pathology. Additionally, we also found that UMAD1 (rs6943429) was nominally associated with Lewy body pathology. Overall, these results contribute to a broader general understanding of how AD risk variants discovered in large-scale clinical genome-wide association studies are involved in the pathological mechanisms of AD and indicate the importance of downstream elimination of phenotypic heterogeneity introduced in these studies. [ABSTRACT FROM AUTHOR]

SUMMARY: Flooding impairs plant growth through oxygen deprivation, which activates plant survival and acclimation responses. Transcriptional responses to low oxygen are generally associated with the activation of group VII ETHYLENE‐RESPONSE FACTOR (ERFVII) transcription factors. However, the exact mechanisms and molecular components by which ERFVII factors initiate gene expression are not fully elucidated. Here, we show that the ERFVII factors RELATED TO APETALA 2.2 (RAP2.2) and RAP2.12 cooperate with the Mediator complex subunit AtMED25 to coordinate gene expression under hypoxia in Arabidopsis thaliana. Respective med25 knock‐out mutants display reduced low‐oxygen stress tolerance. AtMED25 physically associates with a distinct set of hypoxia core genes and its loss partially impairs transcription under hypoxia due to decreased RNA polymerase II recruitment. Association of AtMED25 with target genes requires the presence of ERFVII transcription factors. Next to ERFVII protein stabilisation, also the composition of the Mediator complex including AtMED25 is potentially affected by hypoxia stress as shown by protein‐complex pulldown assays. The dynamic response of the Mediator complex to hypoxia is furthermore supported by the fact that two subunits, AtMED8 and AtMED16, are not involved in the establishment of hypoxia tolerance, whilst both act in coordination with AtMED25 under other environmental conditions. We furthermore show that AtMED25 function under hypoxia is independent of ethylene signalling. Finally, functional conservation at the molecular level was found for the MED25‐ERFVII module between A. thaliana and the monocot species Oryza sativa, pointing to a potentially universal role of MED25 in coordinating ERFVII‐dependent transcript responses to hypoxia in plants. [ABSTRACT FROM AUTHOR]

Background: Neuropathic pain results from a defect in the somatosensory nervous system caused by a diversity of etiologies. The effect of current treat-ment with analgesics and surgery is limited. Studies report the therapeutic use of adipose tissue-derived components to treat neuropathic pain as a new treatment modality. Objective: The aim of this systematic review was to investigate the therapeutic clinical efficacy of adipose tissue-derived components on neuro-pathic pain. Methods: PubMed, Medline, Cochrane and Embase databases were searched until August 2023. Clinical studies assessing neuropathic pain after autologous fat grafting or the therapeutic use of adipose tissue-derived com-ponents were included. The outcomes of interest were neuropathic pain and quality of life. Results: In total, 433 studies were identified, of which 109 dupli-cates were removed, 324 abstracts were screened and 314 articles were excluded. In total, ten studies were included for comparison. Fat grafting and cellular stromal vascular fraction were used as treatments. Fat grafting indications were post-mastectomy pain syndrome, neuromas, post-herpetic neuropathy, neuro-pathic scar pain and trigeminal neuropathic pain. In seven studies, neuropathic pain levels decreased, and overall, quality of life did not improve. Conclusions: The therapeutic efficacy of adipose tissue-derived components in the treatment of neuropathic pain remains unclear due to the few performed clinical trials with small sample sizes for various indications. Larger and properly designed (randomized) controlled trials are required. [ABSTRACT FROM AUTHOR]

Rationale: Cervical radiculopathy is initially typically managed conservatively. Surgery is indicated when conservative management fails or with severe/progressive neurological signs. Personalised multimodal physiotherapy could be a promising conservative strategy. However, aggregated evidence on the (cost‐)effectiveness of personalised multimodal physiotherapy compared to surgery with/without post‐operative physiotherapy is lacking. Aim/Objectives: To systematically summarise the literature on the (cost‐)effectiveness of personalised multimodal physiotherapy compared to surgery with or without post‐operative physiotherapy in patients with cervical radiculopathy. Methods: PubMed, Embase, CINAHL, PsycINFO and Web of Science were searched from inception to 1st of March 2023. Primary outcomes were effectiveness regarding costs, arm pain intensity and disability. Neck pain intensity, perceived recovery, quality of life, neurological symptoms, range‐of‐motion, return‐to‐work, medication use, (re)surgeries and adverse events were considered secondary outcomes. Randomised clinical trials comparing personalised multimodal physiotherapy versus surgical approaches with/without post‐operative physiotherapy were included. Two independent reviewers performed study selection, data‐extraction, and risk of bias assessment using the Cochrane RoB 2 and Consolidated Health Economic Evaluation Reporting Standards statement. Certainty of the evidence was determined using Grading of Recommendations, Assessment, Development and Evaluations. Results: From 2109 records, eight papers from two original trials, with 117 participants in total were included. Low certainty evidence showed there were no significant differences on arm pain intensity and disability, except for the subscale 'heavy work' related disability (12 months) and disability at 5–8 years. Cost‐effectiveness was not assessed. There was low certainty evidence that physiotherapy improved significantly less on neck pain intensity, sensory loss and perceived recovery compared to surgery with/without physiotherapy. Low certainty evidence showed there were no significant differences on numbness, range of motion, medication use, and quality of life. No adverse events were reported. Conclusion: Considering the clinical importance of accurate management recommendations and the current low level of certainty, high‐quality cost‐effectiveness studies are needed. [ABSTRACT FROM AUTHOR]

Purpose: In the emerging field of antibody treatments for neurodegenerative diseases, reliable tools are needed to evaluate new therapeutics, diagnose and select patients, monitor disease progression, and assess therapy response. Immuno-PET combines the high affinity and exceptional specificity of monoclonal antibodies with the non-invasive imaging technique positron emission tomography (PET). Its application in neurodegenerative disease brain imaging has been limited due to the marginal uptake across the blood–brain barrier (BBB). The emergence of BBB-shuttle antibodies with enhanced uptake across the BBB extended immuno-PET to brain imaging. We recently reported about specific brain uptake of a bispecific aducanumab mTfR antibody in APP/PS1 TG mice using 89Zr-immuno-PET. However, a sufficient target-to-background ratio was reached at a relatively late scanning time point of 7 days post-injection. To investigate if a better target-to-background ratio could be achieved earlier, an aducanumab BBB-shuttle with a mutated Fc region for reduced FcRn affinity was evaluated. Procedures: AduH310A-8D3 and Adu-8D3 were modified with DFO*-NCS and subsequently radiolabeled with 89Zr. The potential influence of the H310A mutation, modification with DFO*-NCS, and subsequent radiolabeling on the in vitro binding to amyloid-beta and mTfR1 was investigated via amyloid-beta peptide ELISA and FACS analysis using mTfR1 transfected CHO-S cells. Blood kinetics, brain uptake, in vivo PET imaging and target engagement of radiolabeled AduH310A-8D3 were evaluated and compared to non-mutated Adu-8D3 in APP/PS1 TG mice and wild-type animals as controls. Results: Radiolabeling was performed with sufficient radiochemical yields and radiochemical purity. In vitro binding to amyloid-beta and mTfR1 showed no impairment. [89Zr]Zr-AduH310A-8D3 showed faster blood clearance and earlier differentiation of amyloid-beta-related brain uptake compared to [89Zr]Zr-Adu-8D3. However, only half of the brain uptake was observed for [89Zr]Zr-AduH310A-8D3. Conclusions: Although a faster blood clearance of AduH310A-8D3 was observed, it was concluded that no beneficial effects for 89Zr-immuno-PET imaging of brain uptake were obtained. [ABSTRACT FROM AUTHOR]

Purpose: Hepatic fibrosis develops as a response to chronic liver injury, resulting in the formation of fibrous scars. This process is initiated and driven by collagen-producing activated myofibroblasts which reportedly express high levels of platelet derived growth factor receptor-β (PDGFRβ). We therefore regard PDGFRβ as an anchor for diagnosis and therapy. The Fibrobody® SP02SP26-ABD is a biparatopic VHH-construct targeting PDGFRβ. Here, we explore its potential as a theranostic vector for liver fibrosis. Methods: Specificity, cross-species binding, and cellular uptake of SP02SP26-ABD was assessed using human, mouse and rat PDGFRβ ectodomains and PDGFRβ-expressing cells. Cellular uptake by PDGFRβ-expressing cells was also evaluated by equipping the Fibrobody® with auristatinF and reading out in vitro cytotoxicity. The validity of PDGFRβ as a marker for active fibrosis was confirmed in human liver samples and 3 mouse models of liver fibrosis (DDC, CCl4, CDA-HFD) through immunohistochemistry and RT-PCR. After radiolabeling of DFO*-SP02SP26-ABD with 89Zr, its in vivo targeting ability was assessed in healthy mice and mice with liver fibrosis by PET-CT imaging, ex vivo biodistribution and autoradiography. Results: SP02SP26-ABD shows similar nanomolar affinity for human, mouse and rat PDGFRβ. Cellular uptake and hence subnanomolar cytotoxic potency of auristatinF-conjugated SP02SP26-ABD was observed in PDGFRβ-expressing cell lines. Immunohistochemistry of mouse and human fibrotic livers confirmed co-localization of PDGFRβ with markers of active fibrosis. In all three liver fibrosis models, PET-CT imaging and biodistribution analysis of [89Zr]Zr-SP02SP26-ABD revealed increased PDGFRβ-specific uptake in fibrotic livers. In the DDC model, liver uptake was 12.15 ± 0.45, 15.07 ± 0.90, 20.23 ± 1.34, and 20.93 ± 4.35%ID/g after 1,2,3 and 4 weeks of fibrogenesis, respectively, compared to 7.56 ± 0.85%ID/g in healthy mice. Autoradiography revealed preferential uptake in the fibrotic (PDGFRβ-expressing) periportal areas. Conclusion: The anti-PDGFRβ Fibrobody® SP02SP26-ABD shows selective and high-degree targeting of activated myofibroblasts in liver fibrosis, and qualifies as a vector for diagnostic and therapeutic purposes. [ABSTRACT FROM AUTHOR]

This study seeks to identify key determinants of women empowerment in Nepal using a rich set of socio-demographic and socio-economic characteristics as well as behavioral factors and regional indicators. Results showed that older age is generally associated with higher empowerment across all these domains, while partner controlling behavior tended to decrease empowerment in beliefs about violence and control over sexuality. Education level and wealth were correlated with increased empowerment in control over sexuality and safe sex, though not in the other two domains. Access to media showed mixed effects, reducing empowerment in decision-making but enhancing it in control over sexuality and safe sex. The results suggest that women's empowerment has morphed from the purview of gender equality programs to its current state, where it is considered a broader goal for development. Introduction: Nepal is characterized by low empowerment of women which may have negative effects on their health status as well as sexual and reproductive rights. We seek to identify key determinants of women empowerment in Nepal using a rich set of socio-demographic and socio-economic characteristics as well as behavioral factors and regional indicators. Methods: This study utilizes 4,211 women aged between 15 and 49 years from the 2022 Demographic and Health Survey (DHS) for Nepal. Following the previous study for Mozambique, we use Principal Component Analysis (PCA) to identify components of women's empowerment along three domains: beliefs about violence, decision-making and control over sexuality and safe sex. We use logistic regressions to identify significant predictors of empowerment in each domain and provide crude and adjusted odds ratios along with their 95% confidence intervals. Results: We found that older age is generally associated with higher empowerment across all these domains. Interestingly, while partner controlling behavior tended to decrease empowerment in beliefs about violence and control over sexuality, it was linked to increased decision-making empowerment. Notable regional differences emerged, with higher levels of empowerment observed in the Madhesh and Sudurpashchim regions. Further, education level and wealth were correlated with increased empowerment in control over sexuality and safe sex, though not in the other two domains. Access to media showed mixed effects, reducing empowerment in decision-making but enhancing it in control over sexuality and safe sex. Conclusion: Our results have many similarities but also notable differences with previous literature which emphasizes the importance of regular and region-specific studies of women's empowerment, acknowledging the potential for its change over time and also the prevailing differences across regions. [ABSTRACT FROM AUTHOR]

Truncating genetic variants of SORL1, encoding the endosome recycling receptor SORLA, have been accepted as causal of Alzheimer's disease (AD). However, most genetic variants observed in SORL1 are missense variants, for which it is complicated to determine the pathogenicity level because carriers come from pedigrees too small to be informative for penetrance estimations. Here, we describe three unrelated families in which the SORL1 coding missense variant rs772677709, that leads to a p.Y1816C substitution, segregates with Alzheimer's disease. Further, we investigate the effect of SORLA p.Y1816C on receptor maturation, cellular localization, and trafficking in cell-based assays. Under physiological circumstances, SORLA dimerizes within the endosome, allowing retromer-dependent trafficking from the endosome to the cell surface, where the luminal part is shed into the extracellular space (sSORLA). Our results showed that the p.Y1816C mutant impairs SORLA homodimerization in the endosome, leading to decreased trafficking to the cell surface and less sSORLA shedding. These trafficking defects of the mutant receptor can be rescued by the expression of the SORLA 3Fn-minireceptor. Finally, we find that iPSC-derived neurons with the engineered p.Y1816C mutation have enlarged endosomes, a defining cytopathology of AD. Our studies provide genetic as well as functional evidence that the SORL1 p.Y1816C variant is causal for AD. The partial penetrance of the mutation suggests this mutation should be considered in clinical genetic screening of multiplex early-onset AD families. [ABSTRACT FROM AUTHOR]

PTEN hamartoma tumor syndrome (PHTS) might be associated with a distinct cognitive and psychological profile. However, previous studies are limited, predominantly based on small and pediatric cohorts, likely affected by selection bias, and show a broad range of findings. We aimed to characterize the neuropsychological functioning of adults with PHTS. A total of 40 participants, with intellectual disability as exclusion criterium, completed an extensive clinical neuropsychological assessment including cognitive tasks, questionnaires, and a clinical diagnostic interview. The cognitive tasks and questionnaire data were categorized as below and above average based on 1.5 SD. About 80% of participants showed an average level of intelligence. In addition, 30% and 24% of participants scored below average on immediate memory recall and speed of information processing, respectively. Furthermore, about 25% reported above average scores on the majority of the questionnaires, indicating psychological distress, signs of alexithymia, and cognitive complaints. Personality of participants was characterized by inflexibility, social withdrawal, and difficulties in recognizing and describing their own emotions. Adults with PHTS demonstrate a heterogeneous yet distinct neuropsychological profile that is characterized by slower information processing, psychological problems, and specific personality traits. These findings provide directions on how to optimize the care and daily lives of adults with PHTS. [ABSTRACT FROM AUTHOR]

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Regular cigarette smoking and cannabis consumption are strongly positively related to each other, yet few studies explore their underlying variation and covariation. We evaluated the genetic and environmental decomposition of variance and covariance of these two traits in twin data from three countries with different social norms and legislation. Data from the Netherlands Twin Register, FinnTwin12/16, and the Minnesota Center for Twin Family Research (total N = 21,617) were analyzed in bivariate threshold models of lifetime regular smoking initiation (RSI) and lifetime cannabis initiation (CI). We ran unstratified models and models stratified by sex and country. Prevalence of RSI was lowest in the Netherlands and prevalence of CI was highest in Minnesota. In the unstratified model, genetic (A) and common environmental factors (C) contributed substantially to the liabilities of RSI (A = 0.47, C = 0.34) and CI (A = 0.28, C = 0.51). The two liabilities were significantly phenotypically (rP = 0.56), genetically (rA = 0.74), and environmentally correlated in the unstratified model (rC = 0.47and rE = 0.48, representing correlations between common and unique environmental factors). The magnitude of phenotypic correlation between liabilities varied by country but not sex (Minnesota rP ~ 0.70, Netherlands rP ~ 0.59, Finland rP ~ 0.45). Comparisons of decomposed correlations could not be reliably tested in the stratified models. The prevalence and association of RSI and CI vary by sex and country. These two behaviors are correlated because there is genetic and environmental overlap between their underlying latent liabilities. There is heterogeneity in the genetic architecture of these traits across country. [ABSTRACT FROM AUTHOR]

Integrating multi-omics data into predictive models has the potential to enhance accuracy, which is essential for precision medicine. In this study, we developed interpretable predictive models for multi-omics data by employing neural networks informed by prior biological knowledge, referred to as visible networks. These neural networks offer insights into the decision-making process and can unveil novel perspectives on the underlying biological mechanisms associated with traits and complex diseases. We tested the performance, interpretability and generalizability for inferring smoking status, subject age and LDL levels using genome-wide RNA expression and CpG methylation data from the blood of the BIOS consortium (four population cohorts, Ntotal = 2940). In a cohort-wise cross-validation setting, the consistency of the diagnostic performance and interpretation was assessed. Performance was consistently high for predicting smoking status with an overall mean AUC of 0.95 (95% CI: 0.90–1.00) and interpretation revealed the involvement of well-replicated genes such as AHRR, GPR15 and LRRN3. LDL-level predictions were only generalized in a single cohort with an R2 of 0.07 (95% CI: 0.05–0.08). Age was inferred with a mean error of 5.16 (95% CI: 3.97–6.35) years with the genes COL11A2, AFAP1, OTUD7A, PTPRN2, ADARB2 and CD34 consistently predictive. For both regression tasks, we found that using multi-omics networks improved performance, stability and generalizability compared to interpretable single omic networks. We believe that visible neural networks have great potential for multi-omics analysis; they combine multi-omic data elegantly, are interpretable, and generalize well to data from different cohorts. [ABSTRACT FROM AUTHOR]

Summary: Chronic sleep restriction, common in today's 24/7 society, causes cumulative neurobehavioural impairment, but the dynamics of the build‐up and dissipation of this impairment have not been fully elucidated. We addressed this knowledge gap in a laboratory study involving two, 5‐day periods of sleep restriction to 4 hr per day, separated by a 1‐day dose–response intervention sleep opportunity. We measured sleep physiological and waking neurobehavioural responses in 70 healthy adults, each randomized to one of seven dose–response intervention sleep doses ranging from 0 to 12 hr, or a non‐sleep‐restricted control group. As anticipated, sleep physiological markers showed homeostatic dynamics throughout the study, and waking neurobehavioural impairment accumulated across the two sleep restriction periods. Unexpectedly, there was only a slight and short‐lived effect of the 1‐day dose–response intervention sleep opportunity. Whether the dose–response intervention sleep opportunity involved extension, further restriction or total deprivation of sleep, neurobehavioural functioning during the subsequent second sleep restriction period was dominated by prior sleep–wake history. Our findings revealed a profound and enduring influence of long‐term sleep–wake history as a fundamental aspect of the dynamic regulation of the neurobehavioural response to sleep loss. [ABSTRACT FROM AUTHOR]

Background: Although eMental health interventions are a viable solution to address disparities in access to mental healthcare and increase its efficiency, they still face challenges of implementation. Literature highlights numerous barriers such as diffusion of responsibility and unclear expectations of what implementation entails might hinder this process. While research mostly focuses on analyzing these barriers, there is an urgent need to increase uptake in practice. In turn, commercial companies focus mostly on increasing uptake, while overlooking research outputs. To bridge the gap between research and practice, attention to how implementation occurs in practice is required. This study investigates "Make it Happen" (MiH), the implementation model developed by the eMental Health company Minddistrict, aiming to gain more insight into operationalizing implementation frameworks by 1) describing MiH and its conceptual underpinnings, and 2) gaining lessons learned from the development of MiH. Ultimately, this work aims at improving existing scientific frameworks by extending them with knowledge from practice. Methods: First, individual interviews and focus groups with Minddistrict implementation managers were performed. Second, individual interviews with project leads in mental healthcare organizations that were involved in the implementation of Minddistrict were conducted. Within Minddistrict, 7 implementation managers and account managers were involved, in addition to 11 project leads from mental healthcare organizations. Data were elaborated with thematic analysis. Results: A comprehensive description of MiH and its 5 main phases was achieved. During the 1) Onboarding phase, implementing organizations are guided by Minddistrict to build a team responsible for implementation, which then 2) designs patient and client journeys, 3) builds, tailors and configures their offer, 4) trains key-users and, 5) evaluates the success of implementation. All participants had extensive and aligned definitions and articulated expectations on implementation. Points of improvement for the model such as role ambiguity and excessive workload were identified. As strengths, internal motivation and good relationships with the provider were valued. Conclusion: The present study highlights the importance of clear role division and stakeholder engagement in implementation processes, and suggest that a strong collaboration between companies and academia could optimize implementation efforts and ensure a better fit between humans, context, and technologies. [ABSTRACT FROM AUTHOR]

Ratios of glycerol dialkyl glycerol tetraethers (GDGT), which are membrane lipids of bacteria and archaea, are at the base of several paleoenvironmental proxies. They are frequently applied to soils as well as lake‐ and marine sediments to generate records of past temperature and soil pH. To derive meaningful environmental information from these reconstructions, high analytical reproducibility is required. Based on submitted results by 39 laboratories from across the world, which employ a diverse range of analytical and quantification methods, we explored the reproducibility of brGDGT‐based proxies (MBT′5ME, IR, and #ringstetra) measured on four soil samples and four soil lipid extracts. Correct identification and integration of 5‐ and 6‐methyl brGDGTs is a prerequisite for the robust calculation of proxy values, but this can be challenging as indicated by the large inter‐interlaboratory variation. The exclusion of statistical outliers improves the reproducibility, where the remaining uncertainty translates into a temperature offset from median proxy values of 0.3–0.9°C and a pH offset of 0.05–0.3. There is no apparent systematic impact of the extraction method and sample preparation steps on the brGDGT ratios. Although reported GDGT concentrations are generally consistent within laboratories, they vary greatly between laboratories. This large variability in brGDGT quantification may relate to variations in ionization efficiency or specific mass spectrometer settings possibly impacting the response of brGDGTs masses relative to that of the internal standard used. While ratio values of GDGT are generally comparable, quantities can currently not be compared between laboratories. Key Points: 39 laboratories participated in a round robin to determine the reproducibility of glycerol dialkyl glycerol tetraethers (GDGT) proxy values and quantitiesPeak selection impacts the ratio values and there is no apparent systematic impact of the extraction method and sample preparation stepsQuantification of GDGTs remains a problem, and comparison of GDGT concentrations between laboratories requires further method development [ABSTRACT FROM AUTHOR]

In recent years, there has been growing interest in replacing petroleum-based water-in-oil (W/O) emulsifiers with sustainable and less toxic natural materials. Pickering emulsifiers are considered well-suited candidates due to their high interfacial activity and the ability to form emulsions with long-term stability. However, only sporadic examples of natural materials have been considered as inverse Pickering emulsifiers. This study describes the synthesis of a series of hydrophobic cellulose nanospheres by bulk modification with acyl groups of different chain lengths followed by nanoprecipitation, and their application as inverse emulsifiers. Modification with acyl groups of longer chain length (C16, C18) afforded lower degrees of substitution, but resulted in greater thermal stability than groups with shorter acyl chains (C12, C14). Formation of nanospheres with low aspect ratios and narrow size distributions required low initial cellulose concentrations (< 1% w/v), high volumetric ratios of antisolvent to solvent (> 10:1), and slow addition rates (< 20 mL/h). The modified cellulose nanospheres were able to reduce the interfacial tension between water and hexane from 45.8 mN/m to 31.1 mN/m, with an effect that increased with the number of carbons in the added acyl chains. The stearate-modified nanospheres exhibited superhydrophobic behavior, showing a contact angle of 156° ± 4° with water, and demonstrated emulsification performance comparable to the commonly used molecular surfactant sorbitan stearate. Our findings suggest that hydrophobically modified cellulose nanospheres have the potential to be a bio-derived alternative to traditional molecular W/O emulsifiers. [ABSTRACT FROM AUTHOR]

Obesity is a multifactorial disease associated with low-grade inflammation. The gut is thought to be involved in obesity-related inflammation, as it is continuously exposed to antigens from food, microbiota and metabolites. However, the exact underlying mechanisms are still unknown. Therefore, we examined the relation between gut pathology, microbiota, its metabolites and cytokines in adults with severe obesity. Individuals eligible for bariatric surgery were included. Fecal and plasma samples were collected at surgery timepoint, to assess microbiota and metabolite composition. Jejunal biopsies were collected during surgery and stained for cytotoxic T cells, macrophages, mast cells and tight junction component zonula occludens-1. Based on these stainings, the cohort was divided into four groups: high versus low intestinal inflammation and high versus low intestinal integrity. We found no significant differences in microbiota diversity between groups, nor for individual bacterial species. No significant differences in metabolites were observed between the intestinal inflammatory groups. However, some metabolites and cytokines differed between the intestinal integrity groups. Higher plasma levels of interleukin-8 and tauro-chenodeoxycholic acid were found, whereas isovaleric acid and acetic acid were lower in the high intestinal integrity group. As the results were very subtle, we suggest that our cohort shows very early and minor intestinal pathology. [ABSTRACT FROM AUTHOR]

Establishing methods that allow for more focused management of wildlife under predator pressure may increase the efficiency of managing problematic predators. Non‐invasive dietary analysis and identification of conservation‐sensitive prey in the diet of 'culprit' predator individuals could help to facilitate this and is worthy of exploration. Recently on Phillip Island, Australia, Little Ravens Corvus mellori have emerged as a prominent predator on the clutches of burrow‐nesting Little Penguins Eudyptula minor. We tested the feasibility of using non‐invasive PCR approaches targeting the penguin mitochondrial 16S rRNA marker gene to establish whether penguin DNA could be detected in raven faecal samples, potentially enabling the identification of culprit ravens missed by extensive field observation. Using a metabarcoding approach, we examined the feasibility of non‐invasively establishing other dietary items via high‐throughput amplicon sequencing. We documented components of raven diet using the universal mitochondrial 16S rRNA, insect‐specific 'Chiar' 16S rRNA and plant ITS2. The assemblage of dietary items did not differ with raven culprit status (i.e. a raven previously observed preying upon penguin), sex or date. Penguin was detected in the diet of some individuals classified observationally as non‐culprits. Although some cases may conceivably have been false detections, other explanations include missed depredation events, consumption via scavenging or through secondary consumption (e.g. eating invertebrates that have consumed penguin). While this study found metabarcoding unreliable for unambiguous assigning of raven culprit status, at least as we implemented it, it may hold promise complementing observations if consumption via scavenging can be distinguished from direct depredation. [ABSTRACT FROM AUTHOR]

A key aspect for the applicability of 89Zr‐radioimmunoconjugates is inert modification and radiolabeling. The two commercially available bifunctional variants of the siderophore desferrioxamine (DFO), Fe‐DFO‐N‐suc‐TFP‐ester and p‐NCS‐Bz‐DFO, are most often used for clinical 89Zr‐immuno‐PET. The use of Fe‐DFO‐N‐suc‐TFP‐ester is advantageous with regard to higher radiolysis stability and more facile assessment of radiochemical purity as well as chelator‐to‐mAb ratio. However, not all mAbs withstand the Fe‐removal step at relatively low pH (4–4.5) using EDTA, which is needed after conjugation to allow 89Zr labeling. In this study, it was investigated whether hydroxybenzyl ethylenediamine (HBED) or the clinically approved deferiprone (DFP) can serve as an alternative for EDTA to establish a pH‐independent mild method for Fe‐removal and thereby broaden the applicability of Fe‐DFO‐N‐suc‐TFP‐ester. Carrier‐added [59Fe]Fe‐DFO‐N‐suc‐TFP‐ester was used for mAb modification to enable direct tracking of the Fe‐removal efficiency under various conditions. Whereas incomplete Fe‐removal with HBED was observed at pH 5 or higher, Fe‐removal with DFP was possible at a broad pH range (4–9). This provides a mild, pH‐independent method for Fe‐removal, improving the applicability and attractiveness of Fe‐DFO‐N‐suc‐TFP‐ester for 89Zr‐mAb preparation. [ABSTRACT FROM AUTHOR]

Background: In the Netherlands, university medical centres (UMCs) bear primary responsibility for conducting medical research and delivering highly specialized care. The TopCare program was a policy experiment lasting 4 years in which three non-academic hospitals received funding from the Dutch Ministry of Health to also conduct medical research and deliver highly specialized care in specific domains. This study investigates research collaboration outcomes for all Dutch UMCs and non-academic hospitals in general and, more specifically, for the domains in the non-academic hospitals participating in the TopCare program. Additionally, it explores the organizational boundary work employed by these hospitals to foster productive research collaborations. Methods: A mixed method research design was employed combining quantitative bibliometric analysis of publications and citations across all Dutch UMCs and non-academic hospitals and the TopCare domains with geographical distances, document analysis and ethnographic interviews with actors in the TopCare program. Results: Quantitative analysis shows that, over the period of study, international collaboration increased among all hospitals while national collaboration and single institution research declined slightly. Collaborative efforts correlated with higher impact scores, and international collaboration scored higher than national collaboration. A total of 60% of all non-academic hospitals' publications were produced in collaboration with UMCs, whereas almost 30% of the UMCs' publications were the result of such collaboration. Non-academic hospitals showed a higher rate of collaboration with the UMC that was nearest geographically, whereas TopCare hospitals prioritized expertise over geographical proximity within their specialized domains. Boundary work mechanisms adopted by TopCare hospitals included aligning research activities with organizational mindset (identity), bolstering research infrastructure (competence) and finding and mobilizing strategic partnerships with academic partners (power). These efforts aimed to establish credibility and attractiveness as collaboration partners. Conclusions: Research collaboration between non-academic hospitals and UMCs, particularly where this also involves international collaboration, pays off in terms of publications and impact. The TopCare hospitals used the program's resources to perform boundary work aimed at becoming an attractive and credible collaboration partner for academia. Local factors such as research history, strategic domain focus, in-house expertise, patient flows, infrastructure and network relationships influenced collaboration dynamics within TopCare hospitals and between them and UMCs. [ABSTRACT FROM AUTHOR]

Background: Sleep-related disorders have been associated with cognitive decline and neurodegeneration. American Indians are at increased risk for dementia. Here, we aim to characterize, for the first time, the associations between sleep characteristics and subsequent cognitive performance in a sample of aging American Indians. Methods: We performed analyses on data collected in two ancillary studies from the Strong Heart Study, which occurred approximately 10 years apart with an overlapping sample of 160 American Indians (mean age at follow-up 73.1, standard deviation 5.6; 69.3% female and 80% with high school completion). Sleep measures were derived by polysomnography and self-reported questionnaires, including sleep timing and duration, sleep latency, sleep stages, indices of sleep-disordered breathing, and self-report assessments of poor sleep and daytime sleepiness. Cognitive assessment included measures of general cognition, processing speed, episodic verbal learning, short and long-delay recall, recognition, and phonemic fluency. We performed correlation analyses between sleep and cognitive measures. For correlated variables, we conducted separate linear regressions. We analyzed the degree to which cognitive impairment, defined as more than 1.5 standard deviations below the average Modified Mini Mental State Test score, is predicted by sleep characteristics. All regression analyses were adjusted for age, sex, years of education, body mass index, study site, depressive symptoms score, difference in age from baseline to follow-up, alcohol use, and presence of APOE e4 allele. Results: We found that objective sleep characteristics measured by polysomnography, but not subjective sleep characteristics, were associated with cognitive performance approximately 10 years later. Longer sleep latency was associated with worse phonemic fluency (β = -0.069, p = 0.019) and increased likelihood of being classified in the cognitive impairment group later in life (odds ratio 1.037, p = 0.004). Longer duration with oxygen saturation < 90% was associated with better immediate verbal memory, and higher oxygen saturation with worse total learning, short and long-delay recall, and processing speed. Conclusion: In a sample of American Indians, sleep characteristics in midlife were correlated with cognitive performance a decade later. Sleep disorders may be modifiable risk factors for cognitive impairment and dementia later in life, and suitable candidates for interventions aimed at preventing neurodegenerative disease development and progression. [ABSTRACT FROM AUTHOR]

Previous studies have shown that mothers of naturally conceived dizygotic (DZ) twins tend to be taller, older, and smoke more than mothers of naturally conceived monozygotic (MZ) twin and mothers of singletons. Here, we investigate whether mothers of naturally conceived DZ twins differ from mothers who conceived their DZ twins after medically assisted reproduction (MAR) in eight maternal traits related to fertility based on observational survey data. We include data from 33,648 mothers from the Netherlands Twin Register (NTR) and 1660 mothers of twins from the Norwegian Mother, Father and Child Cohort Study (MoBA). We contrast mothers of naturally conceived DZ twins with mothers of MAR DZ twins. Next, we further segment the MAR group into mothers who underwent hormonal induction of ovulation but not in vitro fertilization (IVF) and those who IVF twins, comparing them both to each other and against the mothers of naturally conceived DZ twins. Mothers of naturally conceived DZ twins smoke more often, differ in body composition, have a higher maternal age and have more offspring before the twins than mothers of MZ twins. Compared to MAR DZ twin mothers, mothers of naturally conceived DZ twins have fewer miscarriages, lower maternal age and increased height, more offspring and are more often smokers. BMI before the twin pregnancy is similar in both natural and MAR DZ twin mothers. Mothers who received hormonal induction of ovulation (OI) have a lower maternal age, fewer miscarriages, and a higher number of offspring before their twin pregnancy than twin mothers who received IVF and/or intracytoplasmic sperm injection (ICSI) treatments. Our study shows that twin mothers are a heterogenous group and the differences between twin mothers should be taken into account in epidemiological and genetic research that includes twins. [ABSTRACT FROM AUTHOR]

Purpose: The introduction of immunotherapy and targeted therapy has drastically improved the life expectancy of patients with advanced cancer. Despite improved survival, obtaining long-term response can be highly distressing and comes with uncertainties that affect several life domains. The aim of this study is to gain a deeper understanding of long-term responders' lived experiences with obtaining long-term response to immunotherapy or targeted therapy. Methods: We conducted an exploratory qualitative study using thematic data analysis. Semi-structured in-depth interviews were conducted with 17 patients with advanced melanoma or lung cancer who had a confirmed response to or long-term stable disease while on immunotherapy or targeted therapy. Results: Long-term responders are living in a twilight zone, where they neither feel like a patient, nor feel healthy. This impacts their self-image, interactions with their social environment, and feelings of uncertainty. Due to their uncertain life perspective, long-term responders are going back and forth between hope and despair, while they are longing for their 'old' life, several barriers, such as protective behavior of the social environment, force them to adjust to a life with cancer. Conclusion: Long-term responders are facing many challenges, such as searching for a renewed identity, dealing with ongoing uncertainty, and having to adapt to a new normal. This emphasizes the importance of providing this new patient group with tailored information and support. Implications for Cancer Survivors: Healthcare professionals can support patients by normalizing their feelings and providing space for varying emotions. Using patient-tailored scan frequencies could help temper fear of progression. [ABSTRACT FROM AUTHOR]

Background: High cognitive activity possibly reduces the risk of cognitive decline and dementia. Aims: To investigate associations between an individual's need to engage in cognitively stimulating activities (need for cognition, NFC) and structural brain damage and cognitive functioning in the Dutch general population with and without existing cognitive impairment. Method: Cross-sectional data were used from the population-based cohort of the Maastricht Study. NFC was measured using the Need For Cognition Scale. Cognitive functioning was tested in three domains: verbal memory, information processing speed, and executive functioning and attention. Values 1.5 s.d. below the mean were defined as cognitive impairment. Standardised volumes of white matter hyperintensities (WMH), cerebrospinal fluid (CSF) and presence of cerebral small vessel disease (CSVD) were derived from 3T magnetic resonance imaging. Multiple linear and binary logistic regression analyses were used adjusted for demographic, somatic and lifestyle factors. Results: Participants (n = 4209; mean age 59.06 years, s.d. = 8.58; 50.1% women) with higher NFC scores had higher overall cognition scores (B = 0.21, 95% CI 0.17–0.26, P < 0.001) and lower odds for CSVD (OR = 0.74, 95% CI 0.60–0.91, P = 0.005) and cognitive impairment (OR = 0.60, 95% CI 0.48–0.76, P < 0.001) after adjustment for demographic, somatic and lifestyle factors. The association between NFC score and cognitive functioning was similar for individuals with and without prevalent cognitive impairment. We found no significant association between NFC and WMH or CSF volumes. Conclusions: A high need to engage in cognitively stimulating activities is associated with better cognitive functioning and less presence of CSVD and cognitive impairment. This suggests that, in middle-aged individuals, motivation to engage in cognitively stimulating activities may be an opportunity to improve brain health. [ABSTRACT FROM AUTHOR]

Chiral higher spin gravity is defined in terms of a strong homotopy algebra of pre-Calabi-Yau type (noncommutative Poisson structure). All structure maps are given by the integrals over the configuration space of concave polygons and the first two maps are related to the (Shoikhet-Tsygan-)Kontsevich Formality. As with the known formality theorems, we prove the A∞-relations via Stokes’ theorem by constructing a closed form and a configuration space whose boundary components lead to the A∞-relations. This gives a new way to formulate higher spin gravities and hints at a construct encompassing the known formality theorems. [ABSTRACT FROM AUTHOR]

The diagnostic spectrum for AML patients is increasingly based on genetic abnormalities due to their prognostic and predictive value. However, information on the AML blast phenotype regarding their maturational arrest has started to regain importance due to its predictive power for drug responses. Here, we deconvolute 1350 bulk RNA-seq samples from five independent AML cohorts on a single-cell healthy BM reference and demonstrate that the morphological differentiation stages (FAB) could be faithfully reconstituted using estimated cell compositions (ECCs). Moreover, we show that the ECCs reliably predict ex-vivo drug resistances as demonstrated for Venetoclax, a BCL-2 inhibitor, resistance specifically in AML with CD14+ monocyte phenotype. We validate these predictions using LUMC proteomics data by showing that BCL-2 protein abundance is split into two distinct clusters for NPM1-mutated AML at the extremes of CD14+ monocyte percentages, which could be crucial for the Venetoclax dosing patients. Our results suggest that Venetoclax resistance predictions can also be extended to AML without recurrent genetic abnormalities and possibly to MDS-related and secondary AML. Lastly, we show that CD14+ monocytic dominated Ven/Aza treated patients have significantly lower overall survival. Collectively, we propose a framework for allowing a joint mutation and maturation stage modeling that could be used as a blueprint for testing sensitivity for new agents across the various subtypes of AML. [ABSTRACT FROM AUTHOR]

Maladaptive personality traits, such as ‘dark personalities’ are found to result in a diverse set of negative outcomes, including paraphilic interests and associated (illegal) behaviors. It is however unclear how these are exactly related, and if related, if then only those individuals higher on dark personality traits and higher impulsivity engage in paraphilic behaviors. In the current study, 50 participants were recruited to investigate the relationship between Dark Tetrad personality traits (i.e., narcissism, psychopathy, Machiavellianism and everyday sadism), paraphilic interests (arousal and behavior) and the moderating role of impulsivity. Personality and paraphilic interests were investigated through self-report questionnaires. Impulsivity was measured both through self-reported dysfunctional impulsivity and the P3 event related potential using electroencephalography during the Go/No-Go task (i.e. response inhibition). The results showed that there was a positive association between psychopathy, sadism and paraphilic interests. Whereas everyday sadism was associated with paraphilic (self-reported) arousal, psychopathy was associated with paraphilic behavior. Although P3 amplitude was not associated with paraphilic interests, self-reported dysfunctional impulsivity was associated with paraphilic behavior specifically. However, there was no moderating role of dysfunctional impulsivity and response inhibition (P3) in the relationship between psychopathy and paraphilic behavior. Findings indicate that the relation between specific dark personalities and paraphilic interests may be more complex than initially thought. Nevertheless, risk assessment and intervention approaches for paraphilia and related behavior both may benefit from incorporating Dark Tetrad and impulsivity measurements. [ABSTRACT FROM AUTHOR]

Background: During the previous two decades, PET imaging of biopharmaceuticals radiolabeled with zirconium-89 has become a consistent tool in preclinical and clinical drug development and patient selection, primarily due to its advantageous physical properties that allow straightforward radiolabeling of antibodies (89Zr-immuno-PET). The extended half-life of 78.4 h permits flexibility with respect to the logistics of tracer production, transportation, and imaging and allows imaging at later points in time. Additionally, its relatively low positron energy contributes to high-sensitivity, high-resolution PET imaging. Considering the growing interest in radiolabeling antibodies, antibody derivatives, and other compound classes with 89Zr in both clinical and pre-clinical settings, there is an urgent need to acquire valuable recommendations and guidelines towards standardization of labeling procedures. Main body: This review provides an overview of the key aspects of 89Zr-radiochemistry and radiopharmaceuticals. Production of 89Zr, conjugation with the mostly used chelators and radiolabeling strategies, and quality control of the radiolabeled products are described in detail, together with discussions about alternative options and critical steps, as well as recommendations for troubleshooting. Moreover, some historical background on 89Zr-immuno-PET, coordination chemistry of 89Zr, and future perspectives are provided. This review aims to serve as a quick-start guide for scientists new to the field of 89Zr-immuno-PET and to suggest approaches for harmonization and standardization of current procedures. Conclusion: The favorable PET imaging characteristics of 89Zr, its excellent availability due to relatively simple production and purification processes, and the development of suitable bifunctional chelators have led to the widespread use of 89Zr. The combination of antibodies and 89Zr, known as 89Zr-immuno-PET, has become a cornerstone in drug development and patient selection in recent years. Despite the advanced state of 89Zr-immuno-PET, new developments in chelator conjugation and radiolabeling procedures, application in novel compound classes, and improved PET scanner technology and quantification methods continue to reshape its landscape towards improving clinical outcomes. [ABSTRACT FROM AUTHOR]

Psychopathy is found to be associated with aggression. However, the role of "understanding the mental states of others" in this relation is not clearly understood yet. The current study aimed to increase our understanding of a specific ability of understanding the mental state of others, namely recognizing a faux pas, and understand the relation of this "social misstep" in self-reported aggressive behavior. The sample consisted of 105 individuals from the community (both males and females) who were tested with the Faux Pas test and several self-report questionnaires assessing triarchic psychopathic personality traits and aggression. We found a positive relationship between the triarchic constructs and self-reported proactive and reactive aggression. Additionally, although all psychopathy constructs were negatively related to self-reported empathy, only the boldness trait was negatively associated with faux pas recognition. No mediation effect of faux pas on the relation between psychopathy and aggression was found. Current findings underline the importance of differentiating different Theory of Mind and empathic abilities in relation to psychopathy and aggression, which is essential to develop effective interventions. [ABSTRACT FROM AUTHOR]

Introduction: The transition from hospital to home is often suboptimal, resulting in patients not receiving the necessary allied healthcare after discharge. This may, in turn, lead to delayed recovery, a higher number of readmissions, more emergency department visits and an increase in mortality and healthcare costs. This study aimed to gain insight into patients' experiences, perceptions, and needs regarding hospital‐to‐home transition, focusing on allied healthcare as a first step towards the development of a transitional integrated allied healthcare pathway for patients with complex care needs after hospital discharge. Methods: We conducted semistructured interviews with patients. Participants were recruited from universities and general hospitals in the Amsterdam region between May and July 2023. They were eligible if they (1) were discharged from the hospital minimally 3 and maximally 12 months after admission to an oncologic surgery department, internal medicine department, intensive care unit, or trauma centre, (2) received hospital‐based care from at least one allied healthcare provider, who visited the patient at least twice during hospital admission, (3) spoke Dutch or English and (4) were 18 years or older. Interviews were audio‐recorded and transcribed verbatim. We performed a thematic analysis of the interview data. Results: Nineteen patients were interviewed. Three themes emerged from the analysis. 'Allied healthcare support during transition' depicts patients' positive experiences when they felt supported by allied health professionals during the hospital‐to‐home transition. 'Patient and family involvement' illustrates how much patients value the involvement of their family members during discharge planning. 'Information recall and processing' portrays the challenges of understanding and remembering overwhelming amounts of information, sometimes unclear and provided at the wrong moment. Overall, patients' experiences of transitional care were positive when they were involved in the discharge process. Negative experiences occurred when their preferences for postdischarge communication were ignored. Conclusions: This study suggests that allied health professionals need to continuously collaborate and communicate with each other to provide patients and their families with the personalized support they need. To provide high‐quality and person‐centred care, it is essential to consider how, when, and what information to provide to patients and their families to allow them to contribute to their recovery actively. Patient or Public Contribution: The interview guide for this manuscript was developed with the assistance of patients, who reviewed it and provided us with feedback. Furthermore, patients provided us with their valuable lived experiences by participating in the interviews conducted for this study. [ABSTRACT FROM AUTHOR]

Background: Transforaminal epidural injections with steroids (TESI) are increasingly being used in patients sciatica. The STAR (steroids against radiculopathy)-trial aimed to evaluate the (cost-) effectiveness of TESI in patients with acute sciatica (< 8 weeks). This article contains the economic evaluation of the STAR-trial. Methods: Participants were randomized to one of three study arms: Usual Care (UC), that is oral pain medication with or without physiotherapy, n = 45); intervention group 1: UC and transforaminal epidural steroid injection (TESI) 1 ml of 0.5% Levobupivacaine and 1 ml of 40 mg/ml Methylprednisolone and intervention group 2: UC and transforaminal epidural injection (TEI) with 1 ml of 0,5% Levobupivacaine and 1 ml of 0.9% NaCl (n = 50). The primary effect measure was health-related quality of life. Secondary outcomes were pain, functioning, and recovery. Costs were measured from a societal perspective, meaning that all costs were included, irrespective of who paid or benefited. Missing data were imputed using multiple imputation, and bootstrapping was used to estimate statistical uncertainty. Results: None of the between-group differences in effects were statistically significant for any of the outcomes (QALY, back pain, leg pain, functioning, and global perceived effect) at the 26-weeks follow-up. The adjusted mean difference in total societal costs was €1718 (95% confidence interval [CI]: − 3020 to 6052) for comparison 1 (intervention group 1 versus usual care), €1640 (95%CI: − 3354 to 6106) for comparison 2 (intervention group 1 versus intervention group 2), and €770 (95%CI: − 3758 to 5702) for comparison 3 (intervention group 2 versus usual care). Except for the intervention costs, none of the aggregate and disaggregate cost differences were statistically significant. The maximum probability of all interventions being cost-effective compared to the control was low (< 0.7) for all effect measures. Conclusion: These results suggest that adding TESI (or TEI) to usual care is not cost-effective compared to usual care in patients with acute sciatica (< 8 weeks) from a societal perspective in a Dutch healthcare setting. Trial registration: Dutch National trial register: NTR4457 (March, 6th, 2014). [ABSTRACT FROM AUTHOR]

Background: The evolution of eHealth development has shifted from standalone tools to comprehensive digital health environments, fostering data exchange among diverse stakeholders and systems. Nevertheless, existing research and implementation frameworks have primarily emphasized technological and organizational aspects of eHealth implementation, overlooking the intricate legal, ethical, and financial considerations. It is essential to discover what legal, ethical, financial, and technological challenges should be considered to ensure successful and sustainable implementation of eHealth. Objective: This review aims to provide insights into barriers and facilitators of legal, ethical, financial, and technological aspects for successful implementation of complex eHealth technologies, which impacts multiple levels and multiple stakeholders. Methods: A scoping review was conducted by querying PubMed, Scopus, Web of Science, and ACM Digital Library (2018-2023) for studies describing the implementation process of eHealth technologies that facilitate data exchange. Studies solely reporting clinical outcomes or conducted outside Europe were excluded. Two independent reviewers selected the studies. A conceptual framework was constructed through axial and inductive coding, extracting data from literature on legal, ethical, financial, and technological aspects of eHealth implementation. This framework guided systematic extraction and interpretation. Results: The search resulted in 7.308 studies that were screened for eligibility, of which 35 (0.48%) were included. Legal barriers revolve around data confidentiality and security, necessitating clear regulatory guidelines. Ethical barriers span consent, responsibility, liability, and validation complexities, necessitating robust frameworks. Financial barriers stem from inadequate funding, requiring (commercial) partnerships and business models. Technological issues include interoperability, integration, and malfunctioning, necessitating strategies for enhancing data reliability, improving accessibility, and aligning eHealth technology with existing systems for smoother integration. Conclusions: This research highlights the multifaceted nature of eHealth implementation, encompassing legal, ethical, financial, and technological considerations. Collaborative stakeholder engagement is paramount for effective decision-making and aligns with the transition from standalone eHealth tools to integrated digital health environments. Identifying suitable stakeholders and recognizing their stakes and values enriches implementation strategies with expertise and guidance across all aspects. Future research should explore the timing of these considerations and practical solutions for regulatory compliance, funding, navigation of responsibility and liability, and business models for reimbursement strategies. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a chronic condition characterized by glucose fluctuations. Laboratory studies suggest that cognition is reduced when glucose is very low (hypoglycemia) and very high (hyperglycemia). Until recently, technological limitations prevented researchers from understanding how naturally-occurring glucose fluctuations impact cognitive fluctuations. This study leveraged advances in continuous glucose monitoring (CGM) and cognitive ecological momentary assessment (EMA) to characterize dynamic, within-person associations between glucose and cognition in naturalistic environments. Using CGM and EMA, we obtained intensive longitudinal measurements of glucose and cognition (processing speed, sustained attention) in 200 adults with T1D. First, we used hierarchical Bayesian modeling to estimate dynamic, within-person associations between glucose and cognition. Consistent with laboratory studies, we hypothesized that cognitive performance would be reduced at low and high glucose, reflecting cognitive vulnerability to glucose fluctuations. Second, we used data-driven lasso regression to identify clinical characteristics that predicted individual differences in cognitive vulnerability to glucose fluctuations. Large glucose fluctuations were associated with slower and less accurate processing speed, although slight glucose elevations (relative to person-level means) were associated with faster processing speed. Glucose fluctuations were not related to sustained attention. Seven clinical characteristics predicted individual differences in cognitive vulnerability to glucose fluctuations: age, time in hypoglycemia, lifetime severe hypoglycemic events, microvascular complications, glucose variability, fatigue, and neck circumference. Results establish the impact of glucose on processing speed in naturalistic environments, suggest that minimizing glucose fluctuations is important for optimizing processing speed, and identify several clinical characteristics that may exacerbate cognitive vulnerability to glucose fluctuations. [ABSTRACT FROM AUTHOR]

Numerous studies have proven the potential of cytokeratin 19 fragment 21-1 (CYFRA 21-1) detection in the (early) diagnosis and treatment monitoring of non-small cell lung cancer (NSCLC). Conventional immunoassays for CYFRA 21-1 quantification are however prone to interferences and lack diagnostic sensitivity and standardization. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is an emerging approach based on a different, often superior, detection principle, which may improve the clinical applicability of CYFRA 21-1 in cancer diagnostics. Therefore, we developed and validated a protein precipitation, immunoaffinity (IA) LC-MS/MS assay for quantitative analysis of serum CYFRA 21-1. Selective sample preparation was performed using ammonium sulfate (AS) precipitation, IA purification, tryptic digestion and LC-MS/MS quantification using a signature peptide and isotopically labeled internal standard. The workflow was optimized and validated according to EMA guidelines and results were compared to a conventional immunoassay. Significant interference effects were seen during IA purification, which were sufficiently solved by performing AS precipitation prior to IA purification. A linear calibration curve was obtained in the range of 1.0–100 ng/mL (R2=0.98). Accuracy and precision were well within acceptance criteria. In sera of patients suspected of lung cancer, the method showed good correlation with the immunoassay. A robust AS precipitation-IA LC-MS/MS assay for the quantification of serum CYFRA 21-1 was developed. With this assay, the clinically added value of LC-MS/MS-based detection over immunoassays can be further explored. [ABSTRACT FROM AUTHOR]

Tolerance mechanisms to single abiotic stress events are being investigated in different plant species, but how plants deal with multiple stress factors occurring simultaneously is still poorly understood. Here, we introduce Salicornia europaea as a species with an extraordinary tolerance level to both flooding and high salt concentrations. Plants exposed to 0.5 M NaCl (mimicking sea water concentrations) grew larger than plants not exposed to salt. Adding more salt reduced growth, but concentrations up to 2.5 M NaCl were not lethal. Regular tidal flooding with salt water (0.5 M NaCl) did not affect growth or chlorophyll fluorescence, whereas continuous flooding stopped growth while plants survived. Quantitative polymerase chain reaction (qPCR) analysis of plants exposed to 1% oxygen in air revealed induction of selected hypoxia responsive genes, but these genes were not induced during tidal flooding, suggesting that S. europaea did not experience hypoxic stress. Indeed, plants were able to transport oxygen into waterlogged soil. Interestingly, sequential exposure to salt and hypoxic air changed the expression of several but not all genes as compared to their expression upon hypoxia only, demonstrating the potential to use S. europaea to investigate signalling-crosstalk between tolerance reactions to multiple environmental perturbations. The extremophile Salicornia europaea is characterised for its tolerance to high salt and flooding conditions. Here, we studied the effect of multiple and simultaneous environmental perturbations of salinity and waterlogging on its growth. Responses to salt and hypoxia reciprocally affected each other when applied simultaneously, demonstrating the significance to investigate signalling-crosstalk between environmental stress reactions in tolerant species. This article belongs to the Collection Flooding Stress and Hypoxic Responses in Plants. [ABSTRACT FROM AUTHOR]

Food safety is recognized as a major hurdle in the transition toward circular food production systems due to the potential reintroduction and accumulation of chemical contaminants in these food systems. Effectively managing these hazardous contaminants in a risk‐based manner requires quantitative insights into the factors influencing the presence and fate of contaminants in the entire circular food chain. A systematic literature review was performed to gain an up‐to‐date overview of the known factors and their influence on the transfer and accumulation of contaminants. This review focused on the terrestrial circular primary food production system, including the pathways between waste‐ or byproduct‐based fertilizers, soil, crops, animal feed, and farmed animals. This review revealed an imbalance in research regarding the different pathways: studies on the soil‐to‐crop pathway were most abundant. The factors identified can be categorized as compound‐related (intrinsic) factors, such as hydrophobicity, molecular weight, and chain length, and extrinsic factors, such as soil organic matter and carbon, pH, milk yield of cows, crop age, and biomass. Quantitative data on the influence of the identified factors were limited. Most studies quantified the influence of individual factors, whereas only a few studies quantified the combined effect of multiple factors. By providing a holistic insight into the influential factors and the quantification of their influence on the fate of contaminants, this review contributes to the improvement of food safety management for chemical hazards when transitioning to a circular food system. [ABSTRACT FROM AUTHOR]