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The aim was to test the hypothesis that left ventricular (LV) and right ventricular (RV) activation from body surface electrical mapping (CardioInsight 252-electrode vest, Medtronic) identifies optimal cardiac resynchronization therapy (CRT) pacing strategies and outcomes in 30 patients. The LV80, RV80, and BIV80 were defined as the times to 80% LV, RV, or biventricular electrical activation. Smaller differences in the LV80 and RV80 (|LV80-RV80|) with synchronized LV pacing predicted better LV function post-CRT (p = 0.0004) than the LV-paced QRS duration (p = 0.32). Likewise, a lower RV80 was associated with a better pre-CRT RV ejection fraction by CMR (r =  - 0.40, p = 0.04) and predicted post-CRT improvements in myocardial oxygen uptake (p = 0.01) better than the biventricular-paced QRS (p = 0.38), while a lower LV80 with BIV pacing predicted lower post-CRT B-type natriuretic peptide (BNP) (p = 0.02). RV pacing improved LV function with smaller |LV80-RV80| (p = 0.009). In conclusion, 3-D electrical mapping predicted favorable post-CRT outcomes and informed effective pacing strategies.

Abstract Amperometry is a commonly used electrochemical method for studying the process of exocytosis in real-time. Given the high precision of recording that amperometry procedures offer, the volume of data generated can span over several hundreds of megabytes to a few gigabytes and therefore necessitates systematic and reproducible methods for analysis. Though the spike characteristics of amperometry traces in the time domain hold information about the dynamics of exocytosis, these biochemical signals are, more often than not, characterized by time-varying signal properties. Such signals with time-variant properties may occur at different frequencies and therefore analyzing them in the frequency domain may provide statistical validation for observations already established in the time domain. This necessitates the use of time-variant, frequency-selective signal processing methods as well, which can adeptly quantify the dominant or mean frequencies in the signal. The Fast Fourier Transform (FFT) is a well-established computational tool that is commonly used to find the frequency components of a signal buried in noise. In this work, we outline a method for spike-based frequency analysis of amperometry traces using FFT that also provides statistical validation of observations on spike characteristics in the time domain. We demonstrate the method by utilizing simulated signals and by subsequently testing it on diverse amperometry datasets generated from different experiments with various chemical stimulations. To our knowledge, this is the first fully automated open-source tool available dedicated to the analysis of spikes extracted from amperometry signals in the frequency domain.

Abstract A genomic database of all Earth’s eukaryotic species could contribute to many scientific discoveries; however, only a tiny fraction of species have genomic information available. In 2018, scientists across the world united under the Earth BioGenome Project (EBP), aiming to produce a database of high-quality reference genomes containing all ~1.5 million recognized eukaryotic species. As the European node of the EBP, the European Reference Genome Atlas (ERGA) sought to implement a new decentralised, equitable and inclusive model for producing reference genomes. For this, ERGA launched a Pilot Project establishing the first distributed reference genome production infrastructure and testing it on 98 eukaryotic species from 33 European countries. Here we outline the infrastructure and explore its effectiveness for scaling high-quality reference genome production, whilst considering equity and inclusion. The outcomes and lessons learned provide a solid foundation for ERGA while offering key learnings to other transnational, national genomic resource projects and the EBP.

Abstract The European Reference Genome Atlas (ERGA) consortium aims to generate a reference genome catalogue for all of Europe's eukaryotic biodiversity. The biological material underlying this mission, the specimens and their derived samples, are provided through ERGA’s pan-European network. To demonstrate the community’s capability and capacity to realise ERGA’s ambitious mission, the ERGA Pilot project was initiated. In support of the ERGA Pilot effort to generate reference genomes for European biodiversity, the ERGA Sampling and Sample Processing committee (SSP) was formed by volunteer experts from ERGA’s member base. SSP aims to aid participating researchers through (i) establishing standards for and collecting of sample/specimen metadata; (ii) prioritisation of species for genome sequencing; and (iii) development of taxon-specific collection guidelines including logistics support. SSP serves as the entry point for sample providers to the ERGA genomic resource production infrastructure and guarantees that ERGA’s high-quality standards are upheld throughout sample collection and processing. With the volume of researchers, projects, consortia, and organisations with interests in genomics resources expanding, this manuscript shares important experiences and lessons learned during the development of standardised operational procedures and sample provider support. The manuscript details our experiences in incorporating the FAIR and CARE principles, species prioritisation, and workflow development, which could be useful to individuals as well as other initiatives.

In this paper, we utilise optimization methods to determine a frequency-independent phase shift such that two phase-shifted versions of a signal can be summed and the resulting amplitude spectrum is unchanged. A phase difference between two signals is thus defined, which remains constant for all frequencies within a given range. For the intended purpose of this study, we set the frequency range to the audible human hearing range of 16 Hz–20 kHz. We found that a new 3-stage filter method provides a variable phase shifter (i.e., ϕ = 0–360°) without the need for additional amplifiers. In addition, we present a new method that reduces the number of filters necessary, improving both the accuracy and efficiency of current techniques.

Abstract The present opinion is the follow‐up of the conclusions and recommendations of the Scientific Opinion on the re‐evaluation of silicon dioxide (E 551) as a food additive relevant to the safety assessment for all age groups. In addition, the risk assessment of silicon dioxide (E 551) for its use in food for infants below 16 weeks of age is performed. Based on the newly available information on the characterisation of the SAS used as E 551 and following the principles of the 2021 EFSA Guidance on Particle‐TR, the conventional safety assessment has been complemented with nano‐specific considerations. Given the uncertainties resulting from the limitations of the database and in the absence of genotoxicity concern, the Panel considered that it is not appropriate to derive an acceptable daily intake (ADI) but applied the margin of exposure (MOE) approach for the risk assessment. The Panel concluded that the MOE should be at least 36 for not raising a safety concern. The calculated MOEs considering the dietary exposure estimates for all population groups using the refined non‐brand loyal scenario, estimated at the time of the 2018 re‐evaluation, were all above 36. The Panel concluded that E 551 does not raise a safety concern in all population groups at the reported uses and use levels. The use of E 551 in food for infants below 16 weeks of age in FC 13.1.1 and FC 13.1.5.1 does not raise a safety concern at the current exposure levels. The Panel also concluded that the technical data provided support an amendment of the specifications for E 551 laid down in Commission Regulation (EU) No 231/2012. The paucity of toxicological studies with proper dispersion protocol (with the exception of the genotoxicity studies) creates uncertainty in the present assessment of the potential toxicological effects related to the exposure to E 551 nanosize aggregates.

BackgroundPediatric kidney transplantations are rarely performed, and there is limited knowledge about the diversity in current clinical practices across Europe. This study aims to explore the utility of clinical snapshot studies in identifying these disparities, establishing a foundation for future snapshot studies and standardization efforts.MethodsA pilot clinical snapshot study was conducted, with invitations extended to all 109 pediatric kidney transplant centres in Europe. Each participating centre provided pre-, peri-, and postoperative data concerning their most recent thirty transplantations. The primary outcomes encompassed the evaluation of disparities in donor-recipient selection, surgical techniques, post-operative drainage procedures, and immunosuppressive therapy protocols. Secondary outcomes involved the analysis of rejection rates, incidence of infections, and graft survival.ResultsThe study involved 439 patients from fifteen centres (14%) in twelve countries, with varying transplant volumes (range 1–29 transplantations per year) and follow-up periods. Significant differences were found among centres in terms of donor types, cold and warm ischemia time, pre-emptive transplant rates, and kidney transplant drainage methods. The rate of living donors varied between 3% and 90% and the median duration of cold ischemia ranged was 770 min after deceased donation and 147 min after living donation. Basiliximab was the dominant induction therapy, yet steroid withdrawal varied widely. Infection, rejection, and graft survival rates also varied significantly between centres.ConclusionThis study revealed substantial variation in clinical practices among European centres performing pediatric kidney transplantations. These findings could serve as a stimulus for international dialogue and collaboration.

Background: Eradicating inhibitors to restore the effectiveness of Factor VIII (FVIII) is a desirable treatment goal for People with Severe Hemophilia A (PwSHA) and inhibitors, as this enables treatment of bleeding episodes with FVIII concentrates. However, since Immune Tolerance Induction (ITI) is a burdensome and costly treatment, it is important to identify determinants for ITI success to decide if it is worth undertaking ITI. For more effective treatment allocation, there is a need to identify which persons will or will not benefit from ITI. Aim: We aimed to identify determinants of successful ITI in PwSHA and to use these determinants in a clinical prediction model. Methods: German, Brazilian, Dutch, Canadian, and Italian PwSHA who underwent ITI were included. The primary outcome was clinical ITI success, defined by (1) a negative inhibitor titer, and (2) an adequate clinical response to FVIII concentrates. Clinical determinants included F8 genotype, race, age, cumulative exposure days to FVIII, inhibitor titers, and ITI regimen. Genetic determinants included in the analyses were FCGR gene, IL10 CA short tandem repeat, and gene variants. Crude Relative Risks (RR) were calculated for ITI success with 95% Confidence Intervals (95% CI). Results: In total, 224 PwSHA were included (61 German, 51 Brazilian, 45 Dutch, 39 Canadian, and 28 Italian). The median ages at inhibitor development and ITI start were 2-years (Interquartile Range [IQR 1‒3]) and 2-years (IQR 1‒6). The median interval between inhibitor diagnosis and ITI start was 17-weeks (IQR 2‒64). Most ITI trials started with recombinant FVIII (130; 58%) and the median prescribed regimen at ITI start was 43 IU/kg/day (IQR 21‒200). The need for adjuvant therapy and central venous access infection were related to failure, while inhibitor titer at detection < 10 BU/mL, inhibitor titer immediately before ITI start < 10 BU/mL, and peak inhibitor titer ever measured < 100 BU/mL were related to success. Inhibitor peak titer below 100 BU/mL showed the highest chance for ITI success (OR = 11.5, 95% CI 5.5‒24.3, p < 0.001). Conclusion: Historical peak titer below 100 BU/mL was the strongest determinant for ITI success. Genetic analyses will be available by the due date, and we will develop a prediction model to estimate the chance of success.

Immune Tolerance Induction (ITI) is the only treatment to eradicate inhibitors in people with Severe Hemophilia A (SHA). Successful ITI restores Factor VIII (FVIII) tolerance. ITI is demanding and successful in approximately 70% of people. Therefore, identifying predictors of ITI outcome is essential to guide clinical decision-making. We aimed to identify genetic predictors of ITI success in people with SHA and inhibitors who underwent ITI. This observational multicenter study included people with SHA who underwent ITI, between 2015 and 2023. Clinical and patient data including factor VIII gene (F8) mutation type and DNA samples were collected. Successful ITI was defined by a negative inhibitor titer and an adequate response to FVIII concentrates. The associations between ITI success and F8 genotype and 216 candidate predictors including single nucleotide polymorphisms (SNPs) and human leukocyte antigen (HLA)-variants employing a global screening array (GSA), CA dinucleotide Short Tandem Repeat (STR) polymorphisms in the Interleukin (IL)-10 promoter region, and FCGR2/3 gene locus variations were analyzed. Of 204 participants, 147 (72.1%) achieved ITI success. The majority (52.0%) of participants had F8 intron 22 inversion. None of the candidate SNPs/HLA-variants, IL-10 CA dinucleotide STR, or FCGR2/3 gene locus variations were associated with ITI success. F8 large deletions were negatively associated with ITI success (OR = 0.15, 95% CI 0.04‒0.51, p = 0.002). Our study including 204 people with SHA identified F8 large deletions as a predictor of ITI failure. Pooling cohorts may allow the identification of additional genetic predictors of ITI success in the future.

Abstract Background Patients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy. Methods The Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life. Discussion From a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable tumour response. Trial registration ClinicalTrials.gov ID NCT05652673, registration date: 08–12-2022.

Abstract Introduction It is unclear whether neurotoxicity due to the antiretroviral drug efavirenz (EFV) results in neurocognitive impairment in people living with HIV (PLWH). Previously, we found that discontinuing EFV was associated with improved processing speed and attention on neuropsychological assessment. In this imaging study, we investigate potential neural mechanisms underlying this cognitive improvement using a BOLD fMRI task assessing cortical and subcortical functioning. Methods Asymptomatic adult PLWH stable on emtricitabine/tenofovirdisoproxil/efavirenz were randomly (1:2) assigned to continue their regimen (n = 12) or to switch to emtricitabine/tenofovirdisoproxil/rilpivirine (n = 28). At baseline and after 12 weeks, both groups performed the Stop-Signal Anticipation Task, which tests reactive and proactive inhibition (indicative of subcortical and cortical functioning, respectively), involving executive functioning, working memory, and attention. Behavior and BOLD fMRI activation levels related to processing speed and attention Z-scores were assessed in 17 pre-defined brain regions. Results Both groups had comparable patient and clinical characteristics. Reactive inhibition behavioral responses improved for both groups on week 12, with other responses unchanged. Between-group activation did not differ significantly. For reactive inhibition, positive Pearson coefficients were observed for the change in BOLD fMRI activation levels and change in processing speed and attention Z-scores in all 17 regions in participants switched to emtricitabine/tenofovir disoproxil/rilpivirine, whereas in the control group, negative correlation coefficients were observed in 10/17 and 13/17 regions, respectively. No differential pattern was observed for proactive inhibition. Conclusion Potential neural mechanisms underlying cognitive improvement after discontinuing EFV in PLWH were found in subcortical functioning, with our findings suggesting that EFV’s effect on attention and processing speed is, at least partially, mediated by reactive inhibition. Trial Registration Clinicaltrials.gov identifier [NCT02308332].

BACKGROUND: A screening tool to predict response to cardiac resynchronization therapy (CRT) could improve patient selection and outcomes. OBJECTIVE: The purpose of this study was to investigate the feasibility and safety of noninvasive CRT via transcutaneous ultrasonic left ventricular (LV) pacing applied as a screening test before CRT implants. METHODS: P-wave-triggered ultrasound stimuli were delivered during bolus dosing of an echocardiographic contrast agent to simulate CRT noninvasively. Ultrasound pacing was delivered at a variety of LV locations with a range of atrioventricular delays to achieve fusion with intrinsic ventricular activation. Three-dimensional cardiac activation maps were acquired via the Medtronic CardioInsight 252-electrode mapping vest during baseline, ultrasound pacing, and after CRT implantation. A separate control group received only the CRT implants. RESULTS: Ultrasound pacing was achieved in 10 patients with a mean of 81.2 ± 50.8 ultrasound paced beats per patient and up to 20 consecutive beats of ultrasound pacing. QRS width at baseline (168.2 ± 17.8 ms) decreased significantly to 117.3 ± 21.5 ms (P

As the mechanism for worse prognosis after cardiac resynchronization therapy (CRT) upgrades in heart failure patients with RVP dependence (RVP-HF) has clinical implications for patient selection and CRT implementation approaches, this study's objective was to evaluate prognostic implications of cardiac magnetic resonance (CMR) findings and clinical factors in 102 HF patients (23.5% female, median age 66.5 years old, median follow-up 4.8 years) with and without RVP dependence undergoing upgrade and de novo CRT implants. Compared with other CRT groups, RVP-HF patients had decreased survival (p = 0.02), more anterior late-activated LV pacing sites (p = 0.002) by CMR, more atrial fibrillation (p = 0.0006), and higher creatinine (0.002). CMR activation timing at the LV pacing site predicted post-CRT LV functional improvement (p < 0.05), and mechanical activation onset < 34 ms by CMR at the LVP site was associated with decreased post-CRT survival in a model with higher pre-CRT creatinine and B-type natriuretic peptide (AUC 0.89; p < 0.0001); however, only the higher pre-CRT creatinine partially mediated (37%) the decreased survival in RVP-HF patients. In conclusion, RVP-HF had a distinct CMR phenotype, which has important implications for the selection of LV pacing sites in CRT upgrades, and only chronic kidney disease mediated the decreased survival after CRT in RVP-HF.

BACKGROUND: Cardiac resynchronization therapy (CRT) response is complex, and better approaches are required to predict survival and need for advanced therapies. OBJECTIVE: The objective was to use machine learning to characterize multidimensional CRT response and its relationship with long-term survival. METHODS: Associations of 39 baseline features (including cardiac magnetic resonance [CMR] findings and clinical parameters such as glomerular filtration rate [GFR]) with a multidimensional CRT response vector (consisting of post-CRT left ventricular end-systolic volume index [LVESVI] fractional change, post-CRT B-type natriuretic peptide, and change in peak VO2) were evaluated. Machine learning generated response clusters, and cross-validation assessed associations of clusters with 4-year survival. RESULTS: Among 200 patients (median age 67.4 years, 27.0% women) with CRT and CMR, associations with more than 1 response parameter were noted for the CMR CURE-SVD dyssynchrony parameter (associated with post-CRT brain natriuretic peptide [BNP] and LVESVI fractional change) and GFR (associated with peak VO2 and post-CRT BNP). Machine learning defined 3 response clusters: cluster 1 (n = 123, 90.2% survival [best]), cluster 2 (n = 45, 60.0% survival [intermediate]), and cluster 3 (n = 32, 34.4% survival [worst]). Adding the 6-month response cluster to baseline features improved the area under the receiver operating characteristic curve for 4-year survival from 0.78 to 0.86 (P = .02). A web-based application was developed for cluster determination in future patients. CONCLUSION: Machine learning characterizes distinct CRT response clusters influenced by CMR features, kidney function, and other factors. These clusters have a strong and additive influence on long-term survival relative to baseline features.

Artificial intelligence (AI) is a game changer in many fields, including cultural heritage. It supports the planning and preservation of heritage sites and cities, enables the creation of virtual experiences to enrich cultural tourism and engagement, supports research, and increases access and understanding of heritage objects. Despite some impressive examples, the full potential of AI for economic, social, and cultural change is not yet fully visible. Against this background, this article aims to (a) highlight the scope of AI in the field of cultural heritage and innovation, (b) highlight the state of the art of AI technologies for cultural heritage, (c) highlight challenges and opportunities, and (d) outline an agenda for AI, cultural heritage, and innovation.

Spaceborne formaldehyde (HCHO) measurements constitute an excellent proxy for the sources of non-methane volatile organic compounds (NMVOCs). Past studies suggested substantial overestimations of NMVOC emissions in state-of-the-art inventories over major source regions. Here, the QA4ECV (Quality Assurance for Essential Climate Variables) retrieval of HCHO columns from OMI (Ozone Monitoring Instrument) is evaluated against (1) FTIR (Fourier-transform infrared) column observations at 26 stations worldwide and (2) aircraft in situ HCHO concentration measurements from campaigns conducted over the USA during 2012–2013. Both validation exercises show that OMI underestimates high columns and overestimates low columns. The linear regression of OMI and aircraft-based columns gives ΩOMI=0.651Ωairc+2.95×1015 molec.cm-2, with ΩOMI and Ωairc the OMI and aircraft-derived vertical columns, whereas the regression of OMI and FTIR data gives ΩOMI=0.659ΩFTIR+2.02×1015 molec.cm-2. Inverse modelling of NMVOC emissions with a global model based on OMI columns corrected for biases based on those relationships leads to much-improved agreement against FTIR data and HCHO concentrations from 11 aircraft campaigns. The optimized global isoprene emissions (∼445Tgyr-1) are 25 % higher than those obtained without bias correction. The optimized isoprene emissions bear both striking similarities and differences with recently published emissions based on spaceborne isoprene columns from the CrIS (Cross-track Infrared Sounder) sensor. Although the interannual variability of OMI HCHO columns is well understood over regions where biogenic emissions are dominant, and the HCHO trends over China and India clearly reflect anthropogenic emission changes, the observed HCHO decline over the southeastern USA remains imperfectly elucidated.

Abstract Background Polypharmacy is common among patients with a limited life expectancy, even shortly before death. This is partly inevitable, because these patients often have multiple symptoms which need to be alleviated. However, the use of potentially inappropriate medications (PIMs) in these patients is also common. Although patients and relatives are often willing to deprescribe medication, physicians are sometimes reluctant due to the lack of evidence on appropriate medication management for patients in the last phase of life. The aim of the AMUSE study is to investigate whether the use of CDSS-OPTIMED, a software program that gives weekly personalized medication recommendations to attending physicians of patients with a limited life expectancy, improves patients’ quality of life. Methods A multicentre stepped-wedge cluster randomized controlled trial will be conducted among patients with a life expectancy of three months or less. The stepped-wedge cluster design, where the clusters are the different study sites, involves sequential crossover of clusters from control to intervention until all clusters are exposed. In total, seven sites (4 hospitals, 2 general practices and 1 hospice from the Netherlands) will participate in this study. During the control period, patients will receive ‘care as usual’. During the intervention period, CDSS-OPTIMED will be activated. CDSS-OPTIMED is a validated software program that analyses the use of medication based on a specific set of clinical rules for patients with a limited life expectancy. The software program will provide the attending physicians with weekly personalized medication recommendations. The primary outcome of this study is patients’ quality of life two weeks after baseline assessment as measured by the EORTC QLQ-C15-PAL questionnaire, quality of life question. Discussion This will be the first study investigating the effect of weekly personalized medication recommendations to attending physicians on the quality of life of patients with a limited life expectancy. We hypothesize that the CDSS-OPTIMED intervention could lead to improved quality of life in patients with a life expectancy of three months or less. Trial registration This trial is registered at ClinicalTrials.gov (NCT05351281, Registration Date: April 11, 2022).

Volatile organic compounds (VOCs) are key precursors of particulate matter and tropospheric ozone. Although the terrestrial biosphere is by far the largest source of VOCs into the atmosphere, the emissions of biogenic VOCs remain poorly constrained at the regional scale. In this work, we derive top-down biogenic emissions over Europe using weekly averaged TROPOMI formaldehyde (HCHO) data from 2018 to 2021. The systematic bias of the TROPOMI HCHO columns is characterized and corrected for based on comparisons with FTIR data at seven European stations. The top-down fluxes of biogenic, pyrogenic, and anthropogenic VOC sources are optimized using an inversion framework based on the MAGRITTEv1.1 chemistry transport model and its adjoint. The inversion leads to strongly increased isoprene emissions with respect to the MEGAN–MOHYCAN inventory over the model domain (from 8.1 to 18.5 Tg yr−1), which is driven by the high observed TROPOMI HCHO columns in southern Europe. The impact of the inversion on biomass burning VOCs (+13 %) and anthropogenic VOCs (−17 %) is moderate. An evaluation of the optimized HCHO distribution against ground-based remote sensing (FTIR and MAX-DOAS) and in situ data provides generally improved agreement at stations below about 50∘ N but indicates overestimated emissions in northern Scandinavia. Sensitivity inversions show that the top-down emissions are robust with respect to changes in the inversion settings and in the model chemical mechanism, leading to differences of up to 10 % in the total emissions. However, the top-down emissions are very sensitive to the bias correction of the observed columns, as the biogenic emissions are 3 times lower when the correction is not applied. Furthermore, the use of different a priori biogenic emissions has a significant impact on the inversion results due to large differences among bottom-up inventories. The sensitivity run using CAMS-GLOB-BIOv3.1 as a priori emissions in the inversion results in 30 % lower emissions with respect to the optimization using MEGAN–MOHYCAN. In regions with large temperature and cloud cover variations, there is strong week-to-week variability in the observed HCHO columns. The top-down emissions, which are optimized at weekly increments, have a much improved capability of representing these large fluctuations than an inversion using monthly increments.

In psychological science, replicability—repeating a study with a new sample achieving consistent results (Parsons et al., 2022)—is critical for affirming the validity of scientific findings. Despite its importance, replication efforts are few and far between in psychological science with many attempts failing to corroborate past findings. This scarcity, compounded by the difficulty in accessing replication data, jeopardizes the efficient allocation of research resources and impedes scientific advancement. Addressing this crucial gap, we present the Replication Database (https://forrt-replications.shinyapps.io/fred_explorer), a novel platform hosting 1,239 original findings paired with replication findings. The infrastructure of this database allows researchers to submit, access, and engage with replication findings. The database makes replications visible, easily findable via a graphical user interface, and tracks replication rates across various factors, such as publication year or journal. This will facilitate future efforts to evaluate the robustness of psychological research.

We present one of the first detailed studies on hesitation marking in a sign language. Based on the analysis of a set of monologues and dialogues from the "Corpus NGT" (Crasborn and Zwitserlood 2008; Crasborn, Zwitserlood, and Ros 2008), we describe the form and position of manual and nonmanual markers of hesitation in Sign Language of the Netherlands (NGT). We show that palm-up, used as a hesitation marker, is akin to a "filled pause" in spoken language, both in its formal properties and its distribution. palm-up is regularly used to mark hesitation in dialogues, but far less commonly in monologues, which we suggest indicates that palm-up is used deliberately by signers to signal a delay in signing (cf. e.g., Maclay and Osgood 1959). Other manual markers of hesitation include sign holds and breaks in signing; their form and patterning in the data suggest they are closer to "unfilled pauses" in speech. As for nonmanuals, we show that all instances of hesitation in our data are marked by a change in the direction of eye gaze, suggesting that this is a clear pragmatic cue that signers use--intentionally or not--to signal a planning problem in signing. This fits well with previous observations that eye gaze plays an important role in turn-taking regulation in sign languages (e.g., Baker 1977).

Multiple-choice questions (MCQs) are popular in vocabulary software because they can be scored automatically and are compatible with many input devices (e.g., touchscreens). Answering MCQs is beneficial for learning, especially when learners retrieve knowledge from memory to evaluate plausible answer alternatives. However, such retrieval may not always occur (e.g., with easy-to-guess answers). Therefore, we tested whether we could optimize MCQs for retrieval practice with a "stepwise display," which presents the question before the answer options. This creates an opportunity for cued recall. In an experimental classroom study (N = 75) and three online experiments with adult participants (N = 45, N = 77, and N = 79), participants practiced vocabulary with either standard MCQs or stepwise MCQs: In standard MCQs, a word was presented with three possible translations; in stepwise MCQs, it was shown for 4 s before the translations appeared. In three of the four experiments (Experiments 1, 3a, and 3b), stepwise MCQs enhanced retention significantly compared to standard MCQs, measured by a posttest several days after practice. Benefits of stepwise MCQs were found for different translation directions (Experiments 1 and 3) and both with easy-to-guess answers (noncompetitive answer options, Experiment 1) and hard-to-guess answers (competitive answer options, Experiment 3). However, the effect was most robust for questions with noncompetitive answer options (Experiments 1, 3a, and 3b) and for learners who reported trying to retrieve the answer from memory during the stepwise display (Experiments 1 and 3). Moreover, retention was generally enhanced by competitive, hard-to-guess answer options (Experiments 3a and 3b). Overall, a stepwise display is a promising and easy-to-implement manipulation to optimize MCQs for retrieval practice.

IntroductionAccumulating evidence indicates the importance of T cell immunity in vaccination-induced protection against severe COVID-19 disease, especially against SARS-CoV-2 Variants-of-Concern (VOCs) that more readily escape from recognition by neutralizing antibodies. However, there is limited knowledge on the T cell responses across different age groups and the impact of CMV status after primary and booster vaccination with different vaccine combinations. Moreover, it remains unclear whether age has an effect on the ability of T cells to cross-react against VOCs.MethodsTherefore, we interrogated the Spike-specific T cell responses in healthy adults of the Dutch population across different ages, whom received different vaccine types for the primary series and/or booster vaccination, using IFNɣ ELISpot. Cells were stimulated with overlapping peptide pools of the ancestral Spike protein and different VOCs.ResultsRobust Spike-specific T cell responses were detected in the vast majority of participants upon the primary vaccination series, regardless of the vaccine type (i.e. BNT162b2, mRNA-1273, ChAdOx1 nCoV-19, or Ad26.COV2.S). Clearly, in the 70+ age group, responses were overall lower and showed more variation compared to younger age groups. Only in CMV-seropositive older adults (>70y) there was a significant inverse relation of age with T cell responses. Although T cell responses increased in all age groups after booster vaccination, Spike-specific T cell frequencies remained lower in the 70+ age group. Regardless of age or CMV status, primary mRNA-1273 vaccination followed by BNT162b2 booster vaccination showed limited booster effect compared to the BNT162b2/BNT162b2 or BNT162b2/mRNA-1273 primary-booster regimen. A modest reduction in cross-reactivity to the Alpha, Delta and Omicron BA.1, but not the Beta or Gamma variant, was observed after primary vaccination.DiscussionTogether, this study shows that age, CMV status, but also the primary-booster vaccination regimen influence the height of the vaccination-induced Spike-specific T cell response, but did not impact the VOC cross-reactivity.

Summary: Background: Sotorasib given after immunotherapy could put patients at increased risk of hepatotoxicity. Therefore, there is a need to gain insight into the potential correlation between anti-PD-(L)1 treatment, anti-PD-(L)1 concentrations, sotorasib concentrations, and the incidence of hepatotoxicity during sotorasib. Methods: Patients with KRASG12C-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker cohort study (NCT05221372). Plasma samples were collected prior and during sotorasib treatment for anti-PD-1 and sotorasib concentrations. ALT/AST/ALP/GGT increases were collected prospectively and graded according to CTCAEv5.0. Severe hepatotoxicity was defined as grade ≥3 ALT/AST/ALP/GGT increase. Findings: Of the 91 included patients, 80 (88%) received prior anti-PD-(L)1. Prior anti-PD-(L)1 and prior immune-related hepatotoxicity were associated with a higher incidence of severe hepatotoxicity (35% versus 0%, p = 0.016 and 75% versus 31%, p = 0.019, respectively). Patients with an interval of ≤6 weeks between anti-PD-(L)1 and sotorasib (n = 18) had a significantly higher incidence of severe hepatotoxicity than those with a 6–12 week (n = 24) and ≥12 week (n = 38) interval (83% versus 33% versus 13%, respectively, p

Gait ataxia is one of the most common and impactful consequences of cerebellar dysfunction. Purkinje cells, the sole output neurons of the cerebellar cortex, are often involved in the underlying pathology, but their specific functions during locomotor control in health and disease remain obfuscated. We aimed to describe the effect of gradual adult-onset Purkinje cell degeneration on gaiting patterns in mice, and to determine whether two different mechanisms that both lead to Purkinje cell degeneration cause different patterns in the development of gait ataxia. Using the ErasmusLadder together with a newly developed limb detection algorithm and machine learning-based classification, we subjected mice to a challenging locomotor task with detailed analysis of single limb parameters, intralimb coordination and whole-body movement. We tested two Purkinje cell-specific mouse models, one involving stochastic cell death due to impaired DNA repair mechanisms (Pcp2-Ercc1−/−), the other carrying the mutation that causes spinocerebellar ataxia type 1 (Pcp2-ATXN1[82Q]). Both mouse models showed progressive gaiting deficits, but the sequence with which gaiting parameters deteriorated was different between mouse lines. Our longitudinal approach revealed that gradual loss of Purkinje cell function can lead to a complex pattern of loss of function over time, and that this pattern depends on the specifics of the pathological mechanisms involved. We hypothesize that this variability will also be present in disease progression in patients, and that our findings will facilitate the study of therapeutic interventions in mice, as subtle changes in locomotor abilities can be quantified by our methods.

Abstract We developed a functional ex vivo anthracycline-based sensitivity test. Surgical resection material of primary breast cancer (BC) was used to determine criteria for the ex vivo sensitivity assay based on morphology, proliferation and apoptosis. Subsequently, a proof-of-concept study was performed correlating results of this assay on primary BC biopsies with in vivo response after treatment with anthracycline-containing neoadjuvant chemotherapy (NAC). Cut off values for the ex vivo anthracycline-based sensitivity test were established based on analysis of 21 primary breast tumor samples obtained after surgery. In the proof-of-concept study based on a new set of tumor biopsies, 41 patients were included. Eight biopsies did not contain tumor cells and three patients could not be biopsied for various reasons. In the remaining 30 biopsies, the success rate of the ex vivo test was 77% (23/30); six out of seven failed tests were due to excessive apoptosis, our pre-specified test criteria. Of the 23 patients with a successful ex vivo test result, three patients did not undergo NAC after the biopsy. Here we report the ex vivo anthracycline-based sensitivity assay is feasible on biopsy material and shows 75% concordance between ex vivo outcomes and in vivo MRI response. Unfortunately, the percentage of unsuccessful tests is rather high. This study provides the foundation for further development of ex vivo sensitivity assays.

Abstract Background People living with cardiovascular diseases (CVD) often experience work participation problems. Good work-focused healthcare, defined as the received advice, treatment, and guidance focusing on work participation, can support the patient and work place. However, experiences with work-focused healthcare are generally not always positive which is a barrier for work participation. Therefore, the objective of this study is to gain insight into the work-focused healthcare journey from the perspective of patients with work participation problems due to CVD, to understand their experiences and needs, and to derive opportunities for improving work-focused healthcare service at a system level. Methods Semi-structured interviews, preceded by preparatory assignments, were conducted with 17 patients who experience(d) work participation problems due to CVD. The patient experience journey map (PEJM) approach was used to visualize the patients’ work-focused healthcare journey, including experiences and needs over time and place, from which opportunities to improve work-focused healthcare from the patient’s perspective were derived. Results An aggregated PEJM consisting of six phases was composed and graphically mapped. The first phase, working, represents a period in which CVD health problems and subsequent functional limitations occur. The next two phases, short- and long-term sick leave, represent a period of full sick leave. The last three phases, start-, partial-, and full vocational reintegration, focus on the process of return to work that takes place ranging from a few months up to several years after sick-listing. For each phase the touchpoints, timespan, stakeholders, activities, experiences and needs from the perspective of the patients were identified. Finally, for better work-focused healthcare nine opportunities for improvement were derived from the PEJM, e.g. emphasize the need for work adjustment prior to the medical intervention, provide more personalized advice on handling work limitations, and putting more compelling pressure on the employer to create suitable work positions for their employees. Discussion/conclusion This paper contributes insights to provide a more patient-centered work-focused healthcare trajectory for patients employed in paid jobs when living with CVD. The PEJM provides an understanding of the patients’ perspectives throughout their work-focused healthcare journey and highlights opportunities for improvement towards a better suited and seamless patient journey, Although this research was conducted within the Dutch healthcare system, it can be assumed that the findings on integrated work-focused healthcare are largly transferable to other healthcare systems.

Multiple prognostic biomarkers, including circulating tumour cell (CTC) counts, exist in metastatic castration‐resistant prostate cancer (mCRPC) patients, but none of them have been implemented into daily clinical care. The modified fast aneuploidy screening test‐sequencing system (mFast‐SeqS), which yields a genome‐wide aneuploidy score, is able to reflect the fraction of cell‐free tumour DNA (ctDNA) within cell‐free DNA (cfDNA) and may be a promising biomarker in mCRPC. In this study, we investigated the prognostic value of dichotomized aneuploidy scores (

Cardiac resynchronization therapy (CRT) is an effective therapy for patients who suffer from heart failure and ventricular dyssynchrony such as left bundle branch block (LBBB). When it works, it reverses adverse left ventricular (LV) remodeling and the progression of heart failure. However, CRT response rate is currently as low as 50-65%. In theory, CRT outcome could be improved by allowing clinicians to tailor the therapy through patient-specific lead locations, timing, and/or pacing protocol. However, this also presents a dilemma: there are far too many possible strategies to test during the implantation surgery. Computational models could address this dilemma by predicting remodeling outcomes for each patient before the surgery takes place. Therefore, the goal of this study was to develop a rapid computational model to predict reverse LV remodeling following CRT. We adapted our recently developed computational model of LV remodeling to simulate the mechanics of ventricular dyssynchrony and added a rapid electrical model to predict electrical activation timing. The model was calibrated to quantitatively match changes in hemodynamics and global and local LV wall mass from a canine study of LBBB and CRT. The calibrated model was used to investigate the influence of LV lead location and ischemia on CRT remodeling outcome. Our model results suggest that remodeling outcome varies with both lead location and ischemia location, and does not always correlate with short-term improvement in QRS duration. The results and time frame required to customize and run this model suggest promise for this approach in a clinical setting.

Cardiovascular tissue engineering is a promising approach to develop grafts that, in contrast to current replacement grafts, have the capacity to grow and remodel like native tissues. This approach largely depends on cell-driven tissue growth and remodeling, which are highly complex processes that are difficult to control inside the scaffolds used for tissue engineering. For several tissue engineering approaches, adverse tissue growth and remodeling outcomes were reported, such as aneurysm formation in vascular grafts, and leaflet retraction in heart valve grafts. It is increasingly recognized that the outcome of tissue growth and remodeling, either physiological or pathological, depends at least partly on the establishment of a homeostatic mechanical state, where one or more mechanical quantities in a tissue are maintained in equilibrium. To design long-term functioning tissue engineering strategies, understanding how scaffold parameters such as geometry affect the mechanical state of a construct, and how this state guides tissue growth and remodeling, is therefore crucial. Here, we studied how anisotropic versus isotropic mechanical loading-as imposed by initial scaffold geometry-influences tissue growth, remodeling, and the evolution of the mechanical state and geometry of tissue-engineered cardiovascular constructs in vitro. Using a custom-built bioreactor platform and nondestructive mechanical testing, we monitored the mechanical and geometric changes of elliptical and circular, vascular cell-seeded, polycaprolactone-bisurea scaffolds during 14 days of dynamic loading. The elliptical and circular scaffold geometries were designed using finite element analysis, to induce anisotropic and isotropic dynamic loading, respectively, with similar maximum stretch when cultured in the bioreactor platform. We found that the initial scaffold geometry-induced (an)isotropic loading of the engineered constructs differentially dictated the evolution of their mechanical state and geometry over time, as well as their final structural organization. These findings demonstrate that controlling the initial mechanical state of tissue-engineered constructs via scaffold geometry can be used to influence tissue growth and remodeling and determine tissue outcomes.

BACKGROUND: Mechanisms of sex-based differences in outcomes following cardiac resynchronization therapy (CRT) are poorly understood. OBJECTIVE: To use cardiac magnetic resonance (CMR) to define mechanisms of sex-based differences in outcomes after CRT and describe distinct CMR-based phenotypes of CRT candidates based on sex and non-ischemic/ischemic cardiomyopathy type. MATERIALS AND METHODS: In a prospective study, sex-based differences in three short-term CRT response measures [fractional change in left ventricular end-systolic volume index 6 months after CRT (LVESVI-FC), B-type natriuretic peptide (BNP) 6 months after CRT, change in peak VO2 6 months after CRT], and long-term survival were evaluated with respect to 39 baseline parameters from CMR, exercise testing, laboratory testing, electrocardiograms, comorbid conditions, and other sources. CMR was also used to quantify the degree of left-ventricular mechanical dyssynchrony by deriving the circumferential uniformity ratio estimate (CURE-SVD) parameter from displacement encoding with stimulated echoes (DENSE) strain imaging. Statistical methods included multivariable linear regression with evaluation of interaction effects associated with sex and cardiomyopathy type (ischemic and non-ischemic cardiomyopathy) and survival analysis. RESULTS: Among 200 patients, the 54 female patients (27%) pre-CRT had a smaller CMR-based LVEDVI (p = 0.04), more mechanical dyssynchrony based on the validated CMR CURE-SVD parameter (p = 0.04), a lower frequency of both late gadolinium enhancement (LGE) and ischemic cardiomyopathy (p < 0.0001), a greater RVEF (p = 0.02), and a greater frequency of LBBB (p = 0.01). After categorization of patients into four groups based on cardiomyopathy type (ischemic/non-ischemic cardiomyopathy) and sex, female patients with non-ischemic cardiomyopathy had the lowest CURE-SVD (p = 0.003), the lowest pre-CRT BNP levels (p = 0.01), the lowest post-CRT BNP levels (p = 0.05), and the most favorable LVESVI-FC (p = 0.001). Overall, female patients had better 3-year survival before adjustment for cardiomyopathy type (p = 0.007, HR = 0.45) and after adjustment for cardiomyopathy type (p = 0.009, HR = 0.67). CONCLUSION: CMR identifies distinct phenotypes of female CRT patients with non-ischemic and ischemic cardiomyopathy relative to male patients stratified by cardiomyopathy type. The more favorable short-term response and long-term survival outcomes in female heart failure patients with CRT were associated with lower indexed CMR-based LV volumes, decreased presence of scar associated with prior myocardial infarction and ICM, and greater CMR-based dyssynchrony with the CURE-SVD.