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PurposeTo empirically examine associations between parental opposition towards comprehensive sexuality education (CSE) and religiosity.MethodsA nationally representative survey of Australian parents (N = 2,418) examined opposition towards 40 CSE topics, by parental religiosity and secular/religious school sector.ResultsWhilst opposition to most CSE topics correlated positively with religiosity, even amongst very religious parents, disapproval was minimal (2.8–31.2%; or 9.0–20.2% netted against non-religious parents). Parents with children enrolled in a Catholic school were less likely than secular-school parents to oppose CSE. Those with children at other-faith-schools were more likely to oppose CSE, but again disapproval was minimal (1.2–21.9%; or 1.3–9.4% netted against secular-school parents).DiscussionOnly small minorities of very religious parents and parents with children in religious schools opposed the teaching of various CSE topics. Decision-makers should therefore be cautious about assuming that CSE delivery is not widely supported by particular families.

ABSTRACT: This study investigated the diet–additive interactions of a Lactobacilli-based probiotic (Pro) and postbiotic (Post) on immune parameters and cecal microbiota composition, with subsequent effects on the metabolome in broilers. A completely randomized block design was employed with 2 diets [standard (SD), and challenge (CD)] and 3 additive conditions (Control, Pro, Post) involving 1,368 one-day-old male Ross 308 broilers equally distributed among 36 pens in a 42 d study. Diets were formulated to contain identical nutrient levels, with CD higher than SD in non-starch polysaccharide content by including rye and barley. Total non-specific serum Ig A, M and G concentrations were determined weekly from d14 to 35. Following vaccination, titres of specific antibodies binding Newcastle disease virus (NDV) and infectious bursal disease virus (IBDV) were measured. Microbiota composition was analyzed by 16S rRNA gene sequencing at d14 and 35, and α- and β-diversity indexes (Observed, Chao1, Bray, Jaccard) were calculated. Cecal short-chain fatty acids and the semi-polar metabolome were determined in the Control SD and all CD groups at d35. At d35, a diet–additive interaction was observed on cecal microbiota composition. Within SD, Pro and Post did not affect operational taxonomic units (OTU) abundance (adjusted-P > 0.05) and diversity indexes (P > 0.05). Within CD, Pro and Post affected the relative abundances of 37 and 44 OTUs, respectively (adjusted-P < 0.05), with Post but not Pro affecting β-diversity indexes (P = 0.041 and 0.064 for Bray and Jaccard, respectively). Within CD, Post increased cecal acetate (21%; P = 0.007) and butyrate (41%; P = 0.002) concentration and affected the concentration of 2 metabolites (adjusted-P < 0.05), while Pro affected 240 metabolites (adjusted-P < 0.05). No diet–additive interactions were observed on serum Ig (P > 0.05), except for IgM at d14 (P = 0.004). Diet composition, but not the additives, affected immune status parameters. The Pro and Post affected cecal microbiota composition only under dietary challenging conditions as previously reported for growth.

Visual Reproduction is a condition to measure Visual Spatial Memory as one of the cognitive domains commonly used to measure visuo-spatial memory. Geometric figures serve as stimulus material, and probands have to reproduce the figures from memory through a hand drawing. The scoring of the drawing has subjective elements. This study aims to evaluate the scoring criteria for the Figural Reproduction Test (FRT), part of the Indonesian Neuropsychological Test Battery, and to develop and evaluate an automated scoring system based on computer vision technology (FRT-CVAS). Scoring evaluation conducted by Cohen Kappa analysis, accuracy, sensitivity, and specificity. The analyzes of the three criteria of the manual confirmed a subjective element in the scoring of the shape of triangles by a moderate (0.74) inter-rater agreement; this agreement could be improved to 0.84 by a slight modification of its criteria. FRT-CVAS, based on computer vision’s identification of the different elements of the hand drawing, was developed and trained using 290 drawings. The system was additionally tested by comparing its scoring with the scoring of two independent raters on 120 drawings from a second data set. FRT-CVAS recognized all elements, and its comparison between human raters showed a high accuracy and sensitivity (minimally 0.91), while the specificity was 0.80 for one of the three criteria. FRT-CVAS offers a highly standardized, consistent, precise, and objective output from the first card in the FRT. This approach is advantageous to data-hungry alternatives such as deep learning when applied to the automated scoring of hand drawings with relatively little data available for training.

Background: Owing to increasing antibiotic resistance, the worldwide efficacy of Helicobacter pylori (HP) eradication treatment has decreased. Aim: To determine antimicrobial resistance of HP in primary care. Design & setting: Retrospective cohort study using real-world routine healthcare data from 80 general practices in the Netherlands. Method: Patients with International Classification of Primary Care (ICPC) codes for gastric symptoms or Anatomical Therapeutic Chemical (ATC) codes for acid inhibition in the period 2010–2020 were selected. Main outcomes were antimicrobial resistance of HP, defined as the prescription of a second eradication treatment within 12 months, and clinical remission of gastric symptoms, defined as no usage of acid inhibition 1 year following eradication therapy. Results: We identified 138 455 patients with gastric symptoms and/or acid inhibition use (mean age 57 years [standard deviation 18.2 years], 43% male). A total of 5224 (4%) patients received an HP eradication treatment. A second treatment was prescribed to 416 (8%) of those patients. From these, 380 patients received amoxicillin–clarithromycin, 16 amoxicillin–metronidazole, and 11 clarithromycin–metronidazole as first regimen and were considered antimicrobial resistant. We observed a 0.8% increment per year of patients requiring a second eradication treatment (P = 0.003, 95% confidence interval = 0.33 to 1.22). After successful eradication, 2329/4808 (48%) patients used acid inhibition compared with 355/416 (85%) patients following treatment failure (P

Peat soils store a large part of the global soil carbon stock, which can potentially be lost when they are drained and taken into cultivation, resulting in CO2 emission and land subsidence. Groundwater level (GWL) management has been proposed to mitigate peat oxidation, but may lead to increased emissions of nitrous oxide (N2O) and methane (CH4).The aim of this experiment was to study trade-offs between greenhouse gas emissions from peat soils as a function of GWL. We incubated 1 m deep, 24 cm diameter undisturbed bare soil cores, after removal of the grass layer, from three contrasting Dutch grassland peat sites for 370 days at 16 °C. The cores were subjected to drying-wetting cycles, with the GWL varying between near the soil surface to 160 cm below the surface. We measured gas fluxes of CO2, N2O and CH4 from the soil surface, extracted pore water for DOC and mineral nitrogen analysis, and measured soil hydraulic and shrinkage characteristics.Emissions of CO2 increased after lowering the GWL, but showed different GWL-response curves during rewetting of the soil. On average, highest CO2 emissions of 1.5 g C·m−2 day−1 were found at a GWL of 80 cm below the surface. However, the 0 cm GWL was the only treatment with significantly lower CO2 emissions than other GWLs. Cumulative CO2 emissions differed significantly between sampling sites. Emissions of N2O showed a different response, peaking at GWL heights above −20 cm, particularly after a recent GWL rise. Though not significantly different, the highest N2O emissions were measured at the 0 cm GWL treatment. We confirmed this pattern for N2O in un-replicated soil cores with grass sward, although emission values were lower in these cores due to the root uptake of mineral nitrogen. CH4 emissions or −uptake remained low under any GWL. We conclude that raising the GWL is a successful strategy to reduce CO2 emissions from peat oxidation. However, raising the GWL close to the soil surface could lead to N2O emissions that negate any gains in terms of global warming potential. Our results suggest that raising the GWL in peat grasslands to −20 cm creates such a risk. A constant GWL at the surface (0 cm) would be preferential for mitigating both CO2 and N2O emissions, although such conditions don’t allow for agricultural grass production (mowing or grazing).

To identify older surgical cancer patients at risk of decreased postoperative recovery of physical activity (PA), this study assesses whether preoperative radiological sarcopenia (RS) is associated with a decreased ability to return to baseline PA. RS was defined as decreased psoas muscle mass or -density by gender-specific cut-offs on CT-scans at level of vertebra L3. PA was assessed as steps/day measured with PA tracker and recovery of PA was defined as >90% of preoperative steps/day at 3 months postoperatively. Of 44 included patients aged 65 and over undergoing oncologic surgery, 18 patients (41%) showed RS. Seventeen patients (39%) returned to baseline PA, of which eight patients had RS (47%). RS was not associated with a return to baseline PA (OR: 1.38, 95%CI 0.39–4.92, p = 0.61). In this exploratory study, no association was found between preoperative RS and recovery of PA postoperatively.

BackgroundDigital mental health interventions could sustainably and scalably prevent and reduce loneliness in older adults. We designed an app containing 29 text-based games and a questionnaire-administering chatbot to stimulate intergenerational contact. ObjectiveThis study aims to evaluate the feasibility of a social gaming app in reducing loneliness among older adults by evaluating recruitment strategies, data collection procedures, and gameplay activity. MethodsThis mixed methods study recruited participants via newsletters, articles, and a social media campaign. We used semistructured interviews and descriptive analysis of questionnaire answers and game data to assess feasibility. Key measures included recruitment reach and efficiency, participant demographics, in-app activity, and app usability and engagement feedback. ResultsThe social media campaign reached 192,641 potential participants, resulting in 1363 game downloads. A total of 155 participants (aged 65 years and older: n=34, 21.9% and aged less than 65 years: n=121, 78.1%) provided informed consent, yielding a conversion rate of 0.08%. The recruitment campaign focusing on distanced playful interaction had a significantly (P

The growth of maritime shipping is leading to the creation of larger vessels. However, this expansion in size brings with it several challenges, including the development of maritime infrastructure, the potential for growth in third-world countries, and the emission of greenhouse gases. In response to these challenges, this research explores the feasibility of designing an autonomous ship capable of transporting a single standardized 40 ft. container overseas using mainly passive propulsion methods. Using advanced design tools, including CAD software and CFD simulations, as well as conducting a comprehensive analysis of relevant literature, the designs for a hull and sails were developed, and an overview of the potential active control systems required for autonomous operation was provided. The study also performed an initial analysis of strength, stability, and velocity to validate the design choices. The ship proves to adhere to the basic strength and stability requirements while reaching its maximum hull velocity at certain wind speeds. The results of the study indicate that it is possible to design and manufacture a mainly passively propelled ship capable of transporting a 40 ft. standardized container overseas and rethink the logistics at scale.

BackgroundInfusion of mesenchymal stromal cells (MSCs) has been proposed as immune-modulatory therapy in solid organ transplantation. The use of allogenic MSCs could improve standardization and allow for direct availability of the product.MethodThe nonrandomized phase Ib Neptune clinical trial provided safety and feasibility data on the use of allogenic bone-marrow-derived MSCs, infused in 10 patients at week 25 and 26 post kidney transplantation. Here, we performed detailed analysis on the peripheral blood immune cell composition of these patients up to 52 weeks post transplantation. We used a 40 marker antibody panel with mass cytometry to assess potential effects of MSC therapy on the immune system.ResultsWe showed minor changes in major immune lineages at week 27, 34 and 52 post kidney transplantation after MSC infusion at week 25 and week 26, confirming previous data with regular flow cytometry. However, in a direct comparison between pre- and post MSC infusion, as soon as 4 hours after MSC infusion, we observed a significant increase in cell numbers of B cell and T cell subsets that shared a unique expression of CD11b, CD11c, CD38, CD39, and Ki-67.ConclusionExploring these CD11b+CD11c+CD38+CD39+Ki-67+ B cells and T cells in the context of MSC infusion after kidney transplantation may be a promising avenue to better understand the immunological effects of MSC therapy.

Summary: Background: The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12. Per-protocol vaccine efficacy (VE) against HIV-1 diagnosis from seven to 24 months was 14.1% (95% CI: −22.0% to 39.5%). Immune correlates analysis was performed for markers selected based on prior evidence in efficacy trials and/or nonhuman primate models. Methods: Humoral and cellular immune response markers at Month 7 were evaluated as immune correlates of risk and of protection in a breakthrough case–control cohort (n = 52 cases, 246 non-cases). Primary markers were IgG binding to vaccine-strain gp140, IgG3 binding to diverse Env antigens (IgG3 Env breadth), IgG3 binding to diverse V1V2 antigens (IgG3 V1V2 breadth), antibody-dependent phagocytosis against the vaccine-strain gp140, Env-specific CD4+ and CD8+ T-cell responses, and multi-epitope functions. Findings: No immune markers were statistically significant correlates of risk. IgG3 V1V2 breadth trended toward an inverse association: hazard ratio 0.70 (95% CI: 0.36 to 1.35; p = 0.29) per 10-fold increase and 0.51 (95% CI: 0.21 to 1.24; p = 0.14) in a Cox model with all primary markers. The VE estimate was 11.8% (95% CI: −17.9% to 34.0%) at all IgG3 V1V2 breadth values below 667 weighted geometric mean net MFI; just above this value, the VE estimate sharply increased to 62.6% (95% CI: −17.9% to 89.6%), and further increased to 80.9% (95% CI: −17.9% to 99.5%) at 1471 MFI, the 95th percentile of the marker distribution. Mediation analysis yielded a VE of 35.7% (95% CI: 15.0% to 51.3%) attributable to the vaccine's impact on this marker. Interpretation: The trend in association of greater IgG3 V1V2 antibody breadth with lower likelihood of HIV acquisition is consistent with the identification of antibodies against V1V2 as immune correlates in three other HIV vaccine efficacy trials and suggests that a greater emphasis should be placed on studying this region in the HIV-1 envelope as a vaccine immunogen. Funding: National Institute of Allergy and Infectious Diseases and Janssen Vaccines & Prevention BV.

Introduction Postoperative pancreatic fistula (POPF) occurs in 25% of patients undergoing a high-risk pancreatoduodenectomy (PD) and is a driving cause of major morbidity, mortality, prolonged hospital stay and increased costs after PD. There is a need for perioperative methods to decrease these risks. In recent studies, preoperative chemoradiotherapy in patients with pancreatic ductal adenocarcinoma (PDAC) reduced the rate of POPF seemingly due to radiation-induced pancreatic fibrosis. However, patients with a high risk of POPF mostly have a non-pancreatic periampullary tumour and do not receive radiotherapy. Prospective studies using radiotherapy specifically to reduce the risk of POPF have not been performed. We aim to assess the safety, feasibility and preliminary efficacy of preoperative stereotactic radiotherapy on the future pancreatic neck transection margin to reduce the rate of POPF.Methods and analysis In this multicentre, single-arm, phase II trial, we aim to assess the feasibility and safety of a single fraction of preoperative stereotactic radiotherapy (12 Gy) to a 4 cm area around the future pancreatic neck transection margin in patients at high risk of developing POPF after PD aimed to reduce the risk of grade B/C POPF. Adult patients scheduled for PD for malignant and premalignant periampullary tumours, excluding PDAC, with a pancreatic duct diameter ≤3 mm will be included in centres participating in the Dutch Pancreatic Cancer Group. The primary outcome is the safety and feasibility of single-dose preoperative stereotactic radiotherapy before PD. The most relevant secondary outcomes are grade B/C POPF and the difference in the extent of fibrosis between the radiated and non-radiated (uncinate margin) pancreas. Evaluation of endpoints will be performed after inclusion of 33 eligible patients.Ethics and dissemination Ethical approval was obtained by the Amsterdam UMC’s accredited Medical Research Ethics Committee (METC). All included patients are required to have provided written informed consent. The results of this trial will be used to determine the need for a randomised controlled phase III trial and submitted to a high-impact peer-reviewed medical journal regardless of the study outcome.Trial registration number NL72913 (Central Committee on Research involving Human Subjects Registry) and NCT05641233 (ClinicalTrials).

Introduction The predominant provider payment models in healthcare, particularly fee-for-service, hinder the delivery of high-value care and can encourage healthcare providers to prioritise the volume of care over the value of care. To address these issues, healthcare providers, payers and policymakers are increasingly experimenting with alternative payment models (APMs), such as shared savings (SS) and bundled payment (BP). Despite a growing body of literature on APMs, there is still limited insight into what works in developing and implementing successful APMs, as well as how, why and under what circumstances. This paper presents the protocol for a study that aims to (1) identify these circumstances and reveal the underlying mechanisms through which outcomes are achieved and (2) identify transferrable lessons for successful APMs in practice.Methods and analysis Drawing on realist evaluation principles, this study will employ an iterative three-step approach to elicit a programme theory that describes the relationship between context, mechanisms and outcomes of APMs. The first step involves a literature review to identify the initial programme theory. The second step entails empirical testing of this theory via a multiple case study design including seven SS and BP initiatives in Dutch hospital care. We will use various qualitative and quantitative methods, including interviews with involved stakeholders, document analysis and difference-in-differences analyses. In the final step, these data and the applicable formal theories will be combined to test and refine the (I)PT and address the research objectives.Ethics and dissemination Ethical approval has been granted by the Research Ethics Review Committee of Erasmus School of Health Policy and Management (Project ID ETH2122-0170). Where necessary, informed consent will be obtained from study participants. Among other means, study results will be disseminated through a publicly available manual for stakeholders (eg, healthcare providers and payers), publications in peer-reviewed scientific journals and (inter)national conference presentations.

Summary: Staphylococcus aureus is a major human pathogen, yet the immune factors that protect against infection remain elusive. High titers of opsonic IgG antibodies, achieved in preclinical animal immunization studies, have consistently failed to provide protection in humans. Here, we investigate antibody responses to the conserved S. aureus surface glycan wall teichoic acid (WTA) and detect the presence of WTA-specific IgM and IgG antibodies in the plasma of healthy individuals. Functionally, WTA-specific IgM outperforms IgG in opsonophagocytic killing of S. aureus and protects against disseminated S. aureus bacteremia through passive immunization. In a clinical setting, patients with S. aureus bacteremia have significantly lower WTA-specific IgM but similar IgG levels compared to healthy controls. Importantly, low WTA-IgM levels correlate with disease mortality and impaired bacterial opsonization. Our findings may guide risk stratification of hospitalized patients and inform future design of antibody-based therapies and vaccines against serious S. aureus infection.

IntroductionThe objective of this demand driven research is to co-design an intervention for upper-secondary students that addresses issues of consent and healthy relationships. In this paper, we (university researchers, student co-researchers, school staff), present the engagement framework that has been critical to the project's development and planned implementation.MethodsAn iterative co-design approach grounded in a participatory research approach is currently being adopted. Student co-researchers from three independent secondary schools on Whadjuk Nyungar Country in Boorloo/Perth, Western Australia, have been engaged as co-researchers in the design of the intervention. Supplementary quantitative and qualitative data from students enrolled at each school site is also being collated to further inform the intervention design. Student co-researchers will provide insights on the overarching design of the intervention including: the scope of key concepts they want to learn, interpretation of supplementary data, and the development of contextually relevant educative content.ResultsRetrospective and prospective components of the engagement framework are described and supported with applied examples where applicable. Preliminary results demonstrate the imperative of adopting iterative co-design, and the efficacy of our authentic engagement framework. A draft intervention has been formalized and will soon undergo piloting. The co-design process has already resulted in an intervention that differs from the initial program first conceptualized by university researchers.ConclusionImperative to our engagement framework is centering students as experts of their lived experience. It is anticipated that this engagement framework will provide insights around the feasibility, value, and necessity for authentic engagement of upper-secondary school students in the design of their consent and healthy relationship education.

BackgroundOral anticoagulation therapy (OAC) is the cornerstone treatment for preventing venous thromboembolism and stroke in patients with nonvalvular atrial fibrillation (NVAF). Despite its significance, challenges in adherence and persistence to OAC regimens have been reported, leading to severe health complications. Central to addressing these challenges is the concept of self-efficacy (SE) in medication management. Currently, there is a noticeable gap in available tools specifically designed to measure SE in OAC self-care management, while such tools are crucial for enhancing patient adherence and overall treatment outcomes. ObjectiveThis study aims to develop and validate a novel scale aimed to measure self-care self-efficacy (SCSE) in patients with NVAF under OAC, which is the patients’ Self-Care Self-Efficacy Index in Oral Anticoagulation Therapy Management (SCSE-OAC), for English- and Italian-speaking populations. We also seek to assess patients’ SE in managing their OAC treatment effectively and to explore the relationship between SE levels and sociodemographic and clinical variables. MethodsUsing a multiphase, mixed methods observational study design, we first conceptualize the SCSE-OAC through literature reviews, patient focus groups, and expert consensus. The scale’s content validity will be evaluated through patient and expert reviews, while its construct validity is assessed using exploratory and confirmatory factor analyses, ensuring cross-cultural applicability. Criterion validity will be examined through correlations with clinical outcomes. Reliability will be tested via internal consistency and test-retest reliability measures. The study will involve adult outpatients with NVAF on OAC treatment for a minimum of 3 months, using both e-surveys and paper forms for data collection. ResultsIt is anticipated that the SCSE-OAC will emerge as a reliable and valid tool for measuring SE in OAC self-care management. It will enable identifying patients at risk of poor adherence due to low SE, facilitating targeted educational interventions. The scale’s validation in both English and Italian-speaking populations will underscore its applicability in diverse clinical settings, contributing significantly to personalized patient-centered care in anticoagulation management. ConclusionsThe development and validation of the SCSE-OAC represent a significant advancement in the field of anticoagulation therapy. Validating the index in English- and Italian-speaking populations will enable personalized patient-centered educational interventions, ultimately improving OAC treatment outcomes. The SCSE-OAC’s focus on SCSE introduces a novel approach to identifying and addressing individual patient needs, promoting adherence, and ultimately improving health outcomes. Future endeavors will seek to extend the validation of the SCSE-OAC across diverse cultural and linguistic landscapes, broadening its applicability in global clinical and research settings. This scale-up effort is crucial for establishing a universal standard for measuring SCSE in OAC management, empowering clinicians and researchers worldwide to tailor effective and culturally sensitive interventions. Trial RegistrationClinicalTrials.gov NCT05820854; https://tinyurl.com/2mmypey7 International Registered Report Identifier (IRRID)PRR1-10.2196/51489

Objectives: In March 2023, all societal-level COVID-19 control measures were lifted by the Dutch government. This study was performed to understand the self-experienced burden of this new phase of COVID-19 on the perspectives and behaviors of severely immunocompromised individuals. Methods: This is an observational, descriptive, cross-sectional study in The Netherlands. An online survey was completed by severely immunocompromised individuals, to capture their general well-being (score from 1 = worst to 10 = best), mental and physical health, and daily and social activities during survey conduct and retrospectively for before onset of COVID-19. The survey was open for completion from May 24th until August 7nd, 2023. Results: Of the 236 respondents, 96.6 % had been vaccinated against COVID-19 and 24.6 % were shielding to avoid COVID-19 during survey conduct. The general well-being score for all respondents was 7.5 (±1.2 SD) before onset of the COVID-19 pandemic and 6.9 (±1.6 SD) during survey conduct (P

Background: The adult congenital heart disease (ACHD) population is growing and risk prediction is important to predict adverse outcome and consult patients during their lifecourse. Objectives: This study aims to describe the long-term prognostic value of blood biomarkers in ACHD. Methods: In this prospective observational cohort study, 602 patients with moderate or complex ACHD were included (median age 32.5 years [IQR: 24.7-41.2], 42% female, 90% New York Heart Association I). N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitive-troponin T, growth differentiation factor 15, high-sensitive-C-reactive protein, suppression of tumorigenicity-2 and galectin-3, as well as full blood count, renal function, LDL, and HDL were measured. Cox models were applied to relate the selected biomarkers with the primary end point of all-cause mortality and secondary end point of mortality or heart failure. Standardized HRs adjusted for relevant prognostic factors, including age, sex, and complexity of diagnosis, were reported. Results: Abnormal biomarker levels were present in 424 (70.4%) patients. During a median follow-up of 10.1 years, 41 (6.8%) patients died and 81 (13.5%) developed heart failure. Associations were observed between the primary and secondary end point and red cell distribution width, NT-proBNP, and growth differentiation factor 15. In a multibiomarker model, only NT-proBNP remained associated with mortality (HR: 2.74; 95% CI: 2.01-3.74). NT-proBNP significantly improved the C-statistic of the clinical prediction model (0.85-0.92). Based on NT-proBNP alone, low-risk patients could be identified. Patients with NT-proBNP

Difficulties in executive function (EF) may be causative factors in clinical conditions, including learning disabilities, depression, and anxiety. However, defining the structure of EF is an ongoing issue, although Miyake’s three-factor structure is widely accepted. This study aims to discover the underlying factor structure of EF domains, as measured by five tests and the scores of 840 participants, to establish the domains’ validity and reliability. Five neuropsychological tests were included in the exploratory and confirmatory factor analyses (EFA and CFA): the Digit Span (DS); the Stroop Color Word Test (Stroop Test); the phonemic Verbal Fluency Test (pVFT); the Five Point Test (5PT); and the Trail Making Test (TMT). EFA could be meaningfully performed (KMO = .862, Bartlett’s test: 𝜒2 =1393.169, df 45, p .001) and yielded three factors closely mirroring the three core domains of EF. CFA of the model in which the 5PT loaded on factor 2 showed the best goodness of fit indicators, although the difference with the other three-factor models was small. Currently, these EF tests are available in Indonesia and suitable for use, although obtaining normative scores adjusted for demographic factors is necessary.

Abstract The therapeutic alliance is considered to play an important role in youth treatment. The commonly used versions of the Working Alliance Inventory (WAI) are based on Bordin’s three-dimensional alliance model. However, previous psychometric studies of the WAI did not find this three-dimensional structure in youth psychotherapy. These earlier findings may indicate different perceptions of the alliance by adolescent versus adult patients, but may also be due to methodological shortcomings. The current study aims to address previous study limitations by evaluating the factor structure of the short version of the WAI (WAI-S) in youth treatment in multilevel analysis to address the hierarchical structure of the alliance data. We examined the psychometric properties of the patient (n = 203) and therapist (n = 62) versions of the WAI-S in youth mental health and addiction care and tested four multilevel models of alliance at start of treatment and 2-month follow-up. Our results suggests a two-factor model for youth and a three-dimensional model for their therapist at both time points. Since this is the first study that finds a best fit for a two-dimensional construct of alliance in youth, more research is needed to clarify whether the differences in alliance dimensions are due to measurement differences between the WAI-S for youth and therapists or whether youth and their therapists truly differ in their perceptions of the concept of alliance.

Abstract Introduction The standard treatment for patients with focal drug-resistant epilepsy (DRE) who are not eligible for open brain surgery is the continuation of anti-seizure medication (ASM) and neuromodulation. This treatment does not cure epilepsy but only decreases severity. The PRECISION trial offers a non-invasive, possibly curative intervention for these patients, which consist of a single stereotactic radiotherapy (SRT) treatment. Previous studies have shown promising results of SRT in this patient population. Nevertheless, this intervention is not yet available and reimbursed in the Netherlands. We hypothesize that: SRT is a superior treatment option compared to palliative standard of care, for patients with focal DRE, not eligible for open surgery, resulting in a higher reduction of seizure frequency (with 50% of the patients reaching a 75% seizure frequency reduction at 2 years follow-up). Methods In this waitlist-controlled phase 3 clinical trial, participants are randomly assigned in a 1:1 ratio to either receive SRT as the intervention, while the standard treatments consist of ASM continuation and neuromodulation. After 2-year follow-up, patients randomized for the standard treatment (waitlist-control group) are offered SRT. Patients aged ≥ 18 years with focal DRE and a pretreatment defined epileptogenic zone (EZ) not eligible for open surgery will be included. The intervention is a LINAC-based single fraction (24 Gy) SRT treatment. The target volume is defined as the epileptogenic zone (EZ) on all (non) invasive examinations. The seizure frequency will be monitored on a daily basis using an electronic diary and an automatic seizure detection system during the night. Potential side effects are evaluated using advanced MRI, cognitive evaluation, Common Toxicity Criteria, and patient-reported outcome questionnaires. In addition, the cost-effectiveness of the SRT treatment will be evaluated. Discussion This is the first randomized trial comparing SRT with standard of care in patients with DRE, non-eligible for open surgery. The primary objective is to determine whether SRT significantly reduces the seizure frequency 2 years after treatment. The results of this trial can influence the current clinical practice and medical cost reimbursement in the Netherlands for patients with focal DRE who are not eligible for open surgery, providing a non-invasive curative treatment option. Trial registration Clinicaltrials.gov Identifier: NCT05182437. Registered on September 27, 2021.

Abstract Mechanisms underlying human hepatocyte growth in development and regeneration are incompletely understood. In vitro, human fetal hepatocytes (FH) can be robustly grown as organoids, while adult primary human hepatocyte (PHH) organoids remain difficult to expand, suggesting different growth requirements between fetal and adult hepatocytes. Here, we characterize hepatocyte organoid outgrowth using temporal transcriptomic and phenotypic approaches. FHs initiate reciprocal transcriptional programs involving increased proliferation and repressed lipid metabolism upon initiation of organoid growth. We exploit these insights to design maturation conditions for FH organoids, resulting in acquisition of mature hepatocyte morphological traits and increased expression of functional markers. During PHH organoid outgrowth in the same culture condition as for FHs, the adult transcriptomes initially mimic the fetal transcriptomic signatures, but PHHs rapidly acquire disbalanced proliferation-lipid metabolism dynamics, resulting in steatosis and halted organoid growth. IL6 supplementation, as emerged from the fetal dataset, and simultaneous activation of the metabolic regulator FXR, prevents steatosis and promotes PHH proliferation, resulting in improved expansion of the derived organoids. Single-cell RNA sequencing analyses reveal preservation of their fetal and adult hepatocyte identities in the respective organoid cultures. Our findings uncover mitogen requirements and metabolic differences determining proliferation of hepatocytes changing from development to adulthood.

Abstract Background The treatment response to corticosteroids in patients with sarcoidosis is highly variable. CD4+ T cells are central in sarcoid pathogenesis and their phenotype in peripheral blood (PB) associates with disease course. We hypothesized that the phenotype of circulating T cells in patients with sarcoidosis may correlate with the response to prednisone treatment. Therefore, we aimed to correlate frequencies and phenotypes of circulating T cells at baseline with the pulmonary function response at 3 and 12 months during prednisone treatment in patients with pulmonary sarcoidosis. Methods We used multi-color flow cytometry to quantify activation marker expression on PB T cell populations in 22 treatment-naïve patients and 21 healthy controls (HCs). Pulmonary function tests at baseline, 3 and 12 months were used to measure treatment effect. Results Patients with sarcoidosis showed an absolute forced vital capacity (FVC) increase of 14.2% predicted (± 10.6, p

Abstract Symptoms of asthma and COPD often overlap, and both diseases can co-exist in one patient. The asthma control questionnaire (ACQ) and clinical COPD questionnaire (CCQ) were developed to assess disease burden in respectively asthma or COPD. This study explores the possibility of creating a new questionnaire to assess disease burden in all obstructive lung diseases by integrating and reducing questions of the ACQ and CCQ. Data of patients with asthma, COPD and asthma-COPD overlap (ACO) were collected from a primary and secondary care center. Patients completed ACQ and CCQ on the same day. Linear regression tested correlations. Principal Component Analysis (PCA) was used for item reduction. The secondary cohort with asthma and COPD patients was used for initial question selection (development cohort). These results were reproduced in the primary care cohort and secondary cohort of patients with ACO. The development cohort comprised 252 patients with asthma and 96 with COPD. Correlation between ACQ and CCQ in asthma was R = 0.82, and in COPD R = 0.83. PCA determined a selection of 9 questions. Reproduction in primary care data (asthma n = 1110, COPD n = 1041, ACO = 355) and secondary care data of ACO patients (n = 53) resulted in similar correlations and PCA-derived selection of questions. In conclusion, PCA determined a selection of nine questions of the ACQ and CCQ: working title ‘the Obstructive Lung Disease Questionnaire’. These results suggest that this pragmatic set of questions might be sufficient to assess disease burden in obstructive lung disease in both primary as secondary care.

Abstract The hexameric AAA+ ATPase p97/VCP functions as an essential mediator of ubiquitin-dependent cellular processes, extracting ubiquitylated proteins from macromolecular complexes or membranes by catalyzing their unfolding. p97 is directed to ubiquitylated client proteins via multiple cofactors, most of which interact with the p97 N-domain. Here, we discover that FAM104A, a protein of unknown function also named VCF1 (VCP/p97 nuclear Cofactor Family member 1), acts as a p97 cofactor in human cells. Detailed structure-function studies reveal that VCF1 directly binds p97 via a conserved α-helical motif that recognizes the p97 N-domain with unusually high affinity, exceeding that of other cofactors. We show that VCF1 engages in joint p97 complex formation with the heterodimeric primary p97 cofactor UFD1-NPL4 and promotes p97-UFD1-NPL4-dependent proteasomal degradation of ubiquitylated substrates in cells. Mechanistically, VCF1 indirectly stimulates UFD1-NPL4 interactions with ubiquitin conjugates via its binding to p97 but has no intrinsic affinity for ubiquitin. Collectively, our findings establish VCF1 as an unconventional p97 cofactor that promotes p97-dependent protein turnover by facilitating p97-UFD1-NPL4 recruitment to ubiquitylated targets.

Abstract Background This study explores the repurposing of Auranofin (AF), an anti-rheumatic drug, for treating non-small cell lung cancer (NSCLC) adenocarcinoma and pancreatic ductal adenocarcinoma (PDAC). Drug repurposing in oncology offers a cost-effective and time-efficient approach to developing new cancer therapies. Our research focuses on evaluating AF's selective cytotoxicity against cancer cells, identifying RNAseq-based biomarkers to predict AF response, and finding the most effective co-therapeutic agents for combination with AF. Methods Our investigation employed a comprehensive drug screening of AF in combination with eleven anticancer agents in cancerous PDAC and NSCLC patient-derived organoids (n = 7), and non-cancerous pulmonary organoids (n = 2). Additionally, we conducted RNA sequencing to identify potential biomarkers for AF sensitivity and experimented with various drug combinations to optimize AF's therapeutic efficacy. Results The results revealed that AF demonstrates a preferential cytotoxic effect on NSCLC and PDAC cancer cells at clinically relevant concentrations below 1 µM, sparing normal epithelial cells. We identified Carbonic Anhydrase 12 (CA12) as a significant RNAseq-based biomarker, closely associated with the NF-κB survival signaling pathway, which is crucial in cancer cell response to oxidative stress. Our findings suggest that cancer cells with low CA12 expression are more susceptible to AF treatment. Furthermore, the combination of AF with the AKT inhibitor MK2206 was found to be particularly effective, exhibiting potent and selective cytotoxic synergy, especially in tumor organoid models classified as intermediate responders to AF, without adverse effects on healthy organoids. Conclusion Our research offers valuable insights into the use of AF for treating NSCLC and PDAC. It highlights AF's cancer cell selectivity, establishes CA12 as a predictive biomarker for AF sensitivity, and underscores the enhanced efficacy of AF when combined with MK2206 and other therapeutics. These findings pave the way for further exploration of AF in cancer treatment, particularly in identifying patient populations most likely to benefit from its use and in optimizing combination therapies for improved patient outcomes.