Search

Abstract Background Breast cancer (BC) is the most common cancer in women in the developed world. In order to find developing cancers in an early stage, BC screening is commonly used. In Flanders, screening is performed in and outside an organized breast cancer screening program (BCSP). However, the determinants of BC screening coverage for both screening strategies are yet unknown. Objective To assess the determinants of BC screening coverage in Flanders. Methods Reimbursement data were used to attribute a screening status to each woman in the target population for the years 2008–2016. Yearly coverage data were categorized as screening inside or outside BCSP or no screening. Data were clustered by municipality level. A generalized linear equation model was used to assess the determinants of screening type. Results Over all years and municipalities, the median screening coverage rate inside and outside BCSP was 48.40% (IQR: 41.50–54.40%) and 14.10% (IQR: 9.80–19.80%) respectively. A higher coverage rate outside BSCP was statistically significantly (P

Abstract Background We examined 15 years of key performance indicators (KPIs) of the population-based mammography screening programme (PMSP) in Flanders, Belgium. Methods Individual screening data were linked to the national cancer registry to obtain oncological follow-up. We benchmarked crude KPI results against KPI-targets set by the European guidelines and KPI results of other national screening programmes. Temporal trends were examined by plotting age-standardised KPIs against the year of screening and estimating the Average Annual Percentage Change (AAPC). Results PMSP coverage increased significantly over the period of 15 years (+ 7.5% AAPC), but the increase fell to + 1.6% after invitation coverage was maximised. In 2016, PMSP coverage was at 50.0% and opportunistic coverage was at 14.1%, resulting in a total coverage by screening of 64.2%. The response to the invitations was 49.8% in 2016, without a trend. Recall rate decreased significantly (AAPC -1.5% & -5.0% in initial and subsequent regular screenings respectively) while cancer detection remained stable (AAPC 0.0%). The result was an increased positive predictive value (AAPC + 3.8%). Overall programme sensitivity was stable and was at 65.1% in 2014. In initial screens of 2015, the proportion of DCIS, tumours stage II+, and node negative invasive cancers was 18.2, 31.2, and 61.6% respectively. In subsequent regular screens of 2015, those proportions were 14.0, 24.8, and 65.4% respectively. Trends were not significant. Conclusion Besides a suboptimal attendance rate, most KPIs in the Flemish PMSP meet EU benchmark targets. Nonetheless, there are several priorities for further investigation such as a critical evaluation of strategies to increase screening participation, organising a biennial radiological review of interval cancers, analysing the effect that preceding opportunistic screening has on the KPI for initial screenings, and efforts to estimate the impact on breast cancer mortality.

Abstract We propose magnetic quivers for the complex-symplectic contraction spaces, which are related to implosions and have a natural interpretation in terms of the Moore-Tachikawa category. We use 3-d mirrors to provide computational checks.

Metaproteomics is an increasingly popular methodology that provides information regarding the metabolic functions of specific microbial taxa and has potential for contributing to ocean ecology and biogeochemical studies. A blinded multi-laboratory intercomparison was conducted to assess comparability and reproducibility of taxonomic and functional results and their sensitivity to methodological variables. Euphotic zone samples from the Bermuda Atlantic Time-series Study (BATS) in the North Atlantic Ocean collected by in situ pumps and the autonomous underwater vehicle (AUV) Clio were distributed with a paired metagenome, and one-dimensional (1D) liquid chromatographic data-dependent acquisition mass spectrometry analysis was stipulated. Analysis of mass spectra from seven laboratories through a common bioinformatic pipeline identified a shared set of 1056 proteins from 1395 shared peptide constituents. Quantitative analyses showed good reproducibility: pairwise regressions of spectral counts between laboratories yielded R2 values averaged 0.62±0.11, and a Sørensen similarity analysis of the top 1000 proteins revealed 70 %–80 % similarity between laboratory groups. Taxonomic and functional assignments showed good coherence between technical replicates and different laboratories. A bioinformatic intercomparison study, involving 10 laboratories using eight software packages, successfully identified thousands of peptides within the complex metaproteomic datasets, demonstrating the utility of these software tools for ocean metaproteomic research. Lessons learned and potential improvements in methods were described. Future efforts could examine reproducibility in deeper metaproteomes, examine accuracy in targeted absolute quantitation analyses, and develop standards for data output formats to improve data interoperability. Together, these results demonstrate the reproducibility of metaproteomic analyses and their suitability for microbial oceanography research, including integration into global-scale ocean surveys and ocean biogeochemical models.

Advances in therapeutic approaches for melanoma urge the need for biomarkers that can identify patients at risk for recurrence and to guide treatment. The potential use of liquid biopsies in identifying biomarkers is increasingly being recognized. Here, we present a head‐to‐head comparison of several techniques to analyze circulating tumor cells (CTCs) and cell‐free DNA (cfDNA) in 20 patients with metastatic melanoma. In this study, we investigated whether diagnostic leukapheresis (DLA) combined with multimarker flow cytometry (FCM) increased the detection of CTCs in blood compared to the CellSearch platform. Additionally, we characterized cfDNA at the level of somatic mutations, extent of aneuploidy and genome‐wide DNA methylation. Both CTCs and cfDNA measures were compared to tumor markers and extracranial tumor burden on radiological imaging. Compared to the CellSearch method applied on peripheral blood, DLA combined with FCM increased the proportion of patients with detectable CTCs from 35% to 70% (P = 0.06). However, the median percentage of cells that could be recovered by the DLA procedure was 29%. Alternatively, cfDNA mutation and methylation analysis detected tumor load in the majority of patients (90% and 93% of samples successfully analyzed, respectively). The aneuploidy score was positive in 35% of all patients. From all tumor measurements in blood, lactate dehydrogenase (LDH) levels were significantly correlated to variant allele frequency (P = 0.004). Furthermore, the presence of CTCs in DLA was associated with tumor burden (P

Abstract Eosinophils were previously reported to play a role in intestinal inflammation and fibrosis. Whether this is as a bystander or as an active participant is still up for debate. Moreover, data describing a causal relationship between eosinophils and intestinal fibrosis are scarce. We here aimed to elucidate the role of eosinophils in the pathogenesis of intestinal inflammation and fibrosis. Therefore, we stimulated fibroblasts with (active) eosinophils or with Eosinophil Cationic Protein (ECP), and assessed fibroblast activation via flow cytometry and immunocytochemistry. We observed decreased fibroblast activation when fibroblasts were co-cultured with active eosinophils or after stimulation with ECP in comparison to monoculture conditions, but not in case of co-culturing with inactivated eosinophils. Furthermore, eosinophil depletion in a RAG−/− chronic DSS colitis model resulted in decreased inflammation, but increased development of fibrosis. In this model, we could show increased expression of the anti-inflammatory protein IL-10 and the pro-fibrotic factors IL-1β, FGF-21 and TGF-β3 in the eosinophil-depleted mice compared to the control mice. In conclusion, our in vitro data revealed an anti-fibrotic role for eosinophils. In line, in a chronic murine colitis model, we observed a pro-inflammatory, but an anti-fibrotic, role for eosinophils. Furthermore, we identified an increased presence of anti-inflammatory and pro-fibrotic cytokines in the eosinophil depleted group.

Abstract We investigate the emergence, mutation profile, and dissemination of SARS-CoV-2 lineage B.1.214.2, first identified in Belgium in January 2021. This variant, featuring a 3-amino acid insertion in the spike protein similar to the Omicron variant, was speculated to enhance transmissibility or immune evasion. Initially detected in international travelers, it substantially transmitted in Central Africa, Belgium, Switzerland, and France, peaking in April 2021. Our travel-aware phylogeographic analysis, incorporating travel history, estimated the origin to the Republic of the Congo, with primary European entry through France and Belgium, and multiple smaller introductions during the epidemic. We correlate its spread with human travel patterns and air passenger data. Further, upon reviewing national reports of SARS-CoV-2 outbreaks in Belgian nursing homes, we found this strain caused moderately severe outcomes (8.7% case fatality ratio). A distinct nasopharyngeal immune response was observed in elderly patients, characterized by 80% unique signatures, higher B- and T-cell activation, increased type I IFN signaling, and reduced NK, Th17, and complement system activation, compared to similar outbreaks. This unique immune response may explain the variant's epidemiological behavior and underscores the need for nasal vaccine strategies against emerging variants.

Abstract Safe storage and utilisation of hydrogen is an ongoing area of research, showing potential to enable hydrogen becoming an effective fuel, substituting current carbon-based sources. Hydrogen storage is associated with a high energy cost due to its low density and boiling point, which drives a high price. Clathrates (gas hydrates) are water-based (ice-like) structures incorporating small non-polar compounds such as H2 in cages formed by hydrogen bonded water molecules. Since only water is required to construct the cages, clathrates have been identified as a potential solution for safe storage of hydrogen. In bulk, pure hydrogen clathrate (H2O-H2) only forms in harsh conditions, but confined in nanospaces the properties of water are altered and hydrogen storage at mild pressure and temperature could become possible. Here, specifically a hydrophobic mesoporous silica is proposed as a host material, providing a suitable nano-confinement for ice-like clathrate hydrate. The hybrid silica material shows an important decrease of the pressure required for clathrate formation (approx. 20%) compared to the pure H2O-H2 system. In-situ inelastic neutron scattering (INS) and neutron diffraction (ND) provided unique insights into the interaction of hydrogen with the complex surface of the hybrid material and demonstrated the stability of nano-confined hydrogen clathrate hydrate.

Abstract We present a study of Ξ c 0 → Ξ 0 π 0 $$ {\Xi}_c^0\to {\Xi}^0{\pi}^0 $$ , Ξ c 0 → Ξ 0 η $$ {\Xi}_c^0\to {\Xi}^0\eta $$ , and Ξ c 0 → Ξ 0 η ′ $$ {\Xi}_c^0\to {\Xi}^0{\eta}^{\prime } $$ decays using the Belle and Belle II data samples, which have integrated luminosities of 980 fb −1 and 426 fb −1, respectively. We measure the following relative branching fractions B Ξ c 0 → Ξ 0 π 0 / B Ξ c 0 → Ξ − π + = 0.48 ± 0.02 stat ± 0.03 syst , B Ξ c 0 → Ξ 0 η / B Ξ c 0 → Ξ − π + = 0.11 ± 0.01 stat ± 0.01 syst , B Ξ c 0 → Ξ 0 η ′ / B Ξ c 0 → Ξ − π + = 0.08 ± 0.02 stat ± 0.01 syst $$ {\displaystyle \begin{array}{c}\mathcal{B}\left({\Xi}_c^0\to {\Xi}^0{\pi}^0\right)/\mathcal{B}\left({\Xi}_c^0\to {\Xi}^{-}{\pi}^{+}\right)=0.48\pm 0.02\left(\textrm{stat}\right)\pm 0.03\left(\textrm{syst}\right),\\ {}\mathcal{B}\left({\Xi}_c^0\to {\Xi}^0\eta \right)/\mathcal{B}\left({\Xi}_c^0\to {\Xi}^{-}{\pi}^{+}\right)=0.11\pm 0.01\left(\textrm{stat}\right)\pm 0.01\left(\textrm{syst}\right),\\ {}\mathcal{B}\left({\Xi}_c^0\to {\Xi}^0{\eta}^{\prime}\right)/\mathcal{B}\left({\Xi}_c^0\to {\Xi}^{-}{\pi}^{+}\right)=0.08\pm 0.02\left(\textrm{stat}\right)\pm 0.01\left(\textrm{syst}\right)\end{array}} $$ for the first time, where the uncertainties are statistical (stat) and systematic (syst). By multiplying by the branching fraction of the normalization mode, B Ξ c 0 → Ξ − π + $$ \mathcal{B}\left({\Xi}_c^0\to {\Xi}^{-}{\pi}^{+}\right) $$ , we obtain the following absolute branching fraction results B Ξ c 0 → Ξ 0 π 0 = 6.9 ± 0.3 stat ± 0.5 syst ± 1.3 norm × 10 − 3 , B Ξ c 0 → Ξ 0 η = 1.6 ± 0.2 stat ± 0.2 syst ± 0.3 norm × 10 − 3 , B Ξ c 0 → Ξ 0 η ′ = 1.2 ± 0.3 stat ± 0.1 syst ± 0.2 norm × 10 − 3 , $$ {\displaystyle \begin{array}{c}\mathcal{B}\left({\Xi}_c^0\to {\Xi}^0{\pi}^0\right)=\left(6.9\pm 0.3\left(\textrm{stat}\right)\pm 0.5\left(\textrm{syst}\right)\pm 1.3\left(\operatorname{norm}\right)\right)\times {10}^{-3},\\ {}\mathcal{B}\left({\Xi}_c^0\to {\Xi}^0\eta \right)=\left(1.6\pm 0.2\left(\textrm{stat}\right)\pm 0.2\left(\textrm{syst}\right)\pm 0.3\left(\operatorname{norm}\right)\right)\times {10}^{-3},\\ {}\mathcal{B}\left({\varXi}_c^0\to {\Xi}^0{\eta}^{\prime}\right)=\left(1.2\pm 0.3\left(\textrm{stat}\right)\pm 0.1\left(\textrm{syst}\right)\pm 0.2\left(\operatorname{norm}\right)\right)\times {10}^{-3},\end{array}} $$ where the third uncertainties are from B Ξ c 0 → Ξ − π + $$ \mathcal{B}\left({\Xi}_c^0\to {\Xi}^{-}{\pi}^{+}\right) $$ . The asymmetry parameter for Ξ c 0 → Ξ 0 π 0 $$ {\Xi}_c^0\to {\Xi}^0{\pi}^0 $$ is measured to be α Ξ c 0 → Ξ 0 π 0 = − 0.90 ± 0.15 stat ± 0.23 syst $$ \alpha \left({\Xi}_c^0\to {\Xi}^0{\pi}^0\right)=-0.90\pm 0.15\left(\textrm{stat}\right)\pm 0.23\left(\textrm{syst}\right) $$ .

Abstract Purpose This study aimed to evaluate the accuracy of detecting vertical root fractures in Biodentine™-filled teeth using the Promax 3Dmax cone-beam computed tomography (CBCT) unit compared to periapical radiographs. It tested hypotheses regarding CBCT’s diagnostic superiority in non-root-filled and Biodentine™-root-filled maxillary central incisors and assessed the impact of smaller field of view and lower intensity settings on detection accuracy. Materials and methods Extracted maxillary incisors were divided into groups based on fracture status and root filling material, then placed in a Thiel-embalmed skull to simulate clinical conditions. The teeth were imaged using periapical radiographs and the CBCT unit under different settings. Fracture thickness was measured with microcomputed tomography for accuracy benchmarking. Multiple observers assessed the images, and statistical analyses were conducted to evaluate diagnostic performance. Results Intra-rater reliabilities of consensus scores ranged from good to very good. Specificities were generally higher than sensitivities across all imaging modalities, but sensitivities remained constantly low. None of the Area Under the Curve scores exceeded 0.6, indicating poor overall accuracy for all imaging modalities. Paired comparisons of the area differences under Receiver Operator Characteristic curves revealed no significant differences between the CBCT and periapical radiograph techniques for detecting vertical root fractures in either Biodentine™-filled or non-root-filled teeth. Conclusions There was no significant accuracy improvement of the current CBCT device (Promax 3Dmax, Planmeca, Finland) over periapical radiographs in detecting small vertical root fractures in both non-root-filled and Biodentine™-root-filled maxillary central incisors. A smaller field of view with lower intensity did not enhance detection accuracy. These results highlight the challenges in accurately detecting small VRFs, emphasizing the need for further research and technological advancements in this domain.

Abstract We present the Manually Annotated GONG Filaments in H-alpha Observations (MAGFiLO v1.0) dataset. This dataset contains 10,244 annotated filaments from 1,593 observations captured by the Global Oscillation Network Group (GONG), spanning the years 2011 through 2022. Each annotation details one filament’s segmentation, minimum bounding box, spine, and magnetic field chirality. With a total of over one thousand person-hours of annotation, and a double-blind review process, we ensured high-quality ground-truth data. Our inter-annotator agreement reaches a Kappa score of 0.66. We also verified that the hemispheric preference of filaments as annotated in MAGFiLO aligns with the findings from similar datasets of much smaller sample sizes. MAGFiLO is the first dataset of its size, enabling advanced deep learning models to identify filaments and their features with unprecedented precision. It also provides a testbed for solar physicists interested in large-scale analysis of filaments. In this report, we document the details of the annotation and the post-processing phases that were applied.

We identified a cluster of mpox exposures among key populations in Kenya through retrospective serologic screening. We identified strong seropositivity among sex workers and gay, bisexual, and other men who have sex with men. These findings demonstrate the need for increased mpox surveillance among mpox-endemic and mpox-endemic–adjacent regions in Africa.

Abstract We present measurements of the branching fractions of eight B ¯ 0 $$ {\overline{B}}^0 $$ → D (*)+ K − K S ∗ 0 $$ {K}_{(S)}^{\left(\ast \right)0} $$ , B − → D (*)0 K − K S ∗ 0 $$ {K}_{(S)}^{\left(\ast \right)0} $$ decay channels. The results are based on data from SuperKEKB electron-positron collisions at the Υ(4S) resonance collected with the Belle II detector, corresponding to an integrated luminosity of 362 fb −1. The event yields are extracted from fits to the distributions of the difference between expected and observed B meson energy, and are efficiency-corrected as a function of m(K − K S ∗ 0 $$ {K}_{(S)}^{\left(\ast \right)0} $$ ) and m(D (*) K S ∗ 0 $$ {K}_{(S)}^{\left(\ast \right)0} $$ ) in order to avoid dependence on the decay model. These results include the first observation of B ¯ 0 $$ {\overline{B}}^0 $$ → D + K − K S 0 $$ {K}_S^0 $$ , B − → D* 0 K − K S 0 $$ {K}_S^0 $$ , and B ¯ 0 $$ {\overline{B}}^0 $$ → D* + K − K S 0 $$ {K}_S^0 $$ decays and a significant improvement in the precision of the other channels compared to previous measurements. The helicity-angle distributions and the invariant mass distributions of the K − K S ∗ 0 $$ {K}_{(S)}^{\left(\ast \right)0} $$ systems are compatible with quasi-two-body decays via a resonant transition with spin-parity J P = 1− for the K − K S 0 $$ {K}_S^0 $$ systems and J P = 1+ for the K − K* 0 systems. We also present measurements of the branching fractions of four B ¯ 0 $$ {\overline{B}}^0 $$ → D (*)+ D s − $$ {D}_s^{-} $$ , B − → D (*)0 D s − $$ {D}_s^{-} $$ decay channels with a precision compatible to the current world averages.

Abstract Background By addressing physical and psychosocial needs, group care (GC) improves health-related behaviours, peer support, parent-provider interactions and may improve birth outcomes. Hence, global implementation of GC is encouraged. Context analyses prior to implementation are vital to elucidate which local factors may support or hinder implementation. Methods Contextual analyses conducted in the Netherlands and Suriname were compared to identify the factors relevant to the implementability of GC as perceived by healthcare professionals (HCPs). 32 semi-structured interviews were conducted with Dutch and Surinamese healthcare professionals. Audio recordings were transcribed verbatim and coded using the Framework approach. The Consolidated Framework for Implementation Research guided the development of the interview guide and of the coding tree. Results Outer setting: Concerns regarding funding surfaced in both countries. Due to limited health insurance coverage, additional fees would limit accessibility in Suriname. In the Netherlands, midwives dreaded lower revenue due to reimbursement policies that favour one-on-one care. Inner setting: Appropriate space for GC was absent in one Dutch and three Surinamese facilities. Role division regarding GC implementation was clearer in the Netherlands than in Suriname. Innovation: HCPs from both countries expected increased social support, health knowledge among women, and continuity of care(r). Individuals/innovation deliverers: Self-efficacy and motivation emerged as intertwined determinants to GC implementation in both countries. Individuals/innovation recipients: Competing demands can potentially lower acceptability of GC in both countries. While Dutch HCPs prioritised an open dialogue with mothers, Surinamese HCPs encouraged the inclusion of partners. Process: Campaigns to raise awareness of GC were proposed. Language barriers were a concern for Dutch but not for Surinamese HCPs. Conclusions While the most striking differences between both countries were found in the outer setting, they trickle down and affect all layers of context. Ultimately, at a later stage, the process evaluation will show if those outer setting barriers we identified prior to implementation actually hindered GC implementation. Changes to the health care systems would ensure sustained implementation in both countries, and this conclusion feeds into a more general discussion: how to proceed when contextual analyses reveal barriers that cannot be addressed with the time and resources available.

Abstract Cobas EGFR mutation Test v2 was FDA-approved as qualitative liquid biopsy for actionable EGFR variants in non-small cell lung cancer (NSCLC). It generates semiquantitative index (SQI) values that correlate with mutant allele levels, but decision thresholds for clinical use in NSCLC surveillance are lacking. We conducted long-term ctDNA monitoring in 20 subjects with EGFR-mutated NSCLC; resulting in a 155 on-treatment samples. We defined optimal SQI intervals to predict/rule-out progression within 12 weeks from sampling and performed orthogonal calibration versus deep-sequencing and digital PCR. SQI showed significant diagnostic power (AUC 0.848, 95% CI 0.782–0.901). SQI below 5 (63% of samples) had 93% (95% CI 87–96%) NPV, while SQI above 10 (25% of samples) had 69% (95% CI 56–80%) PPV. Cobas EGFR showed perfect agreement with sequencing (Kappa 0.860; 95% CI 0.674–1.00) and digital PCR. SQI values strongly (r: 0.910, 95% 0.821–0.956) correlated to mutant allele concentrations with SQI of 5 and 10 corresponding to 6–9 (0.2–0.3%) and 64–105 (1.1–1.6%) mutant allele copies/mL (VAF) respectively. Our dual-threshold classifier of SQI 0/5/10 yielded informative results in 88% of blood draws with high NPV and good overall clinical utility for patient-centric surveillance of metastatic NSCLC.

Abstract Current treatment outcome of patients with glioblastoma (GBM) remains poor. Following standard therapy, recurrence is universal with limited survival. Tumors from 173 GBM patients are analysed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoantigens. All patients were treated within the scope of an individual healing attempt. Among all vaccinated patients, including 70 treated prior to progression (primary) and 103 treated after progression (recurrent), the median overall survival from first diagnosis is 31.9 months (95% CI: 25.0–36.5). Adverse events are infrequent and are predominantly grade 1 or 2. A vaccine-induced immune response to at least one of the vaccinated peptides is detected in blood samples of 87 of 97 (90%) monitored patients. Vaccine-specific T-cell responses are durable in most patients. Significantly prolonged survival is observed for patients with multiple vaccine-induced T-cell responses (53 months) compared to those with no/low induced responses (27 months; P = 0.03). Altogether, our results highlight that the application of personalized neoantigen-targeting peptide vaccine is feasible and represents a promising potential treatment option for GBM patients.

Abstract The multi-staged XENON program at INFN Laboratori Nazionali del Gran Sasso aims to detect dark matter with two-phase liquid xenon time projection chambers of increasing size and sensitivity. The XENONnT experiment is the latest detector in the program, planned to be an upgrade of its predecessor XENON1T. It features an active target of 5.9 tonnes of cryogenic liquid xenon (8.5 tonnes total mass in cryostat). The experiment is expected to extend the sensitivity to WIMP dark matter by more than an order of magnitude compared to XENON1T, thanks to the larger active mass and the significantly reduced background, improved by novel systems such as a radon removal plant and a neutron veto. This article describes the XENONnT experiment and its sub-systems in detail and reports on the detector performance during the first science run.

Abstract Background Since 2011 when the Canadian Institutes of Health Research launched the Strategy for Patient Oriented Research, there has been a growing expectation to embed patient-oriented research (POR) in the health research community in Canada. To meet this expectation and build capacity for POR in the field of neurodevelopmental disability and child health, in 2017 researchers and family leaders at CanChild Centre for Childhood Disability Research, McMaster University partnered with Kids Brain Health Network and McMaster Continuing Education to develop and implement a 10-week online Family Engagement in Research (FER) Course. Main text From its inception, the FER Course has been delivered in partnership with family leaders and researchers. The FER Course is innovative in its co-learning and community building approach. The course is designed to bring family partners and researchers together to co-learn and connect, and to develop competency and confidence in both the theory and practice of family engagement in research. Coursework involves four live online group discussions, individual review of course materials, weekly group activities, and a final group project and presentation. Upon completion of the FER Course, graduates earn a McMaster University micro-credential. Conclusions To meet a need in building capacity in POR, a novel course in the field of neurodevelopmental disability and child health has been co-created and delivered. Over six years (2018–2023), the FER Course has trained more than 430 researchers and family partners across 20 countries. A unique outcome of the FER Course is that graduates expressed the wish to stay connected and continue to collaborate well beyond the course in turn creating an international FER Community Network that continues to evolve based on need. The FER Course is creating a growing international community of researchers, trainees, self-advocates, and family partners who are championing the implementation of meaningful engagement in neurodevelopmental disability and child health research and beyond. The course is internationally recognized with an established record of building capacity in POR. Its uptake, sustainability, and scalability to date has illustrated that training programs like the FER Course are necessary for building capacity and leadership in family engagement in research.

Background: Young adults (YA) with cancer often have unmet psychosocial needs. The impact of peer support delivered in an online format to fulfil these needs in the populations of YA with cancer has not been thoroughly examined. Methods: We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, and Medline databases. We included articles about online peer support interventions for YA cancer survivors between the ages of 18 to 40 years old. Results: Our literature search yielded n = 2,773 articles and we obtained consensus on 12 articles for inclusion. We qualitatively synthesized these articles using data abstraction based on the Template for Intervention and Replication (TIDierR) checklist. Overall, six studies demonstrated correlation between online peer support and improved wellbeing of participants. Thus, online peer support may be useful for young cancer patients. Conclusion: This systematic review summarizes the current state of knowledge regarding the availability and evaluation of online YA peer support programs and reveals the need for further research in this field.

Contexte : Il n’est pas rare que les besoins psychosociaux des jeunes adultes atteints de cancer ne soient pas satisfaits. Peu d’études se sont penchées de manière exhaustive sur l’efficacité des ressources de soutien par les pairs en ligne pour répondre aux besoins de cette population. Méthodologie : Une recherche dans les bases de données Cochrane Central Register of Controlled Trials, CINAHL, Embase et Medline a permis de trouver des articles portant sur les interventions de soutien par les pairs à l’intention des jeunes survivants du cancer âgés entre 18 et 40 ans. Résultats : Cette recherche a fait ressortir 2 773 articles, dont 12 ont été retenus par consensus. Les articles ont fait l’objet d’une synthèse qualitative à partir de données extraites à l’aide de la liste de vérification Template for Intervention Description and Replication (TIDieR; modèle pour la description et la reproduction des interventions). En tout, 6 études ont montré l’existence d’une corrélation entre le soutien par les pairs en ligne et l’amélioration du bien-être. Ce type d’intervention pourrait donc être utile pour les jeunes atteints de cancer. Conclusion : La présente revue systématique résume l’état actuel des connaissances sur la disponibilité et l’évaluation des programmes en ligne de soutien par les pairs à l’intention des jeunes; elle révèle également le besoin d’approfondir la recherche dans ce domaine.

The Sustainable Development Goals (SDGs) have set the agenda for 2030, calling for collective global efforts to deal with climate change while seeking a balance between economic development and environmental protection. Although many countries are exploring emission reduction paths, mainly from government and corporate perspectives, addressing climate change is also an individual responsibility and requires public participation in collective action. The millennial generation constitutes the current workforce and will be the leaders in climate action for the next 30 years. Therefore, our study focuses on the Chinese millennial generation, conducting in-depth semi-structured interviews with 50 participants in qualitative research to explore their low-carbon lifestyles, the barriers, and enablers in switching to a wider range of low-carbon lifestyles. There are three main results: (1) Based on our study samples, there is an indication that Chinese millennials have a positive attitude towards transitioning to a low-carbon lifestyle. Women demonstrate a stronger willingness to adopt low-carbon behaviors in their daily household activities compared to men. However, their involvement in governance in the context of transitioning to a low-carbon society is limited, with most women assuming execution roles in climate action rather than decision-making positions. (2) Millennial’s low-carbon life transition is accompanied by technological innovation and progress. However, this progress brings some new forms of resource waste, and reasonable policy-making is essential. (3) Personal economic interests and the satisfaction of their consumption needs will drive millennials to reduce carbon emissions in their daily lives, but it requires the guidance of reasonable policy-making and synergies among various stakeholders. This research will help policymakers better understand the current status and potential issues related to people’s low-carbon actions, enabling the formulation of more rational guiding policies. It can also help other stakeholders learn about millennials’ demands and take more effective collective action toward carbon reduction.

Introduction. Campylobacteriosis is among the leading causes of acute gastrointestinal infections. The severity of campylobacteriosis and the development of long-term complications may be influenced by the genotype of the pathogen, whose biological properties can affect immune response parameters. The aim of the study was to identify common genotypes of epidemic clones of Campylobacter pathogens and to investigate characteristics of the immune response and severity of the disease. Materials and methods. The study included 203 patients aged from 1 month to 17 years with campylobacteriosis who underwent treatment at the clinic of the Federal State Budgetary Institution "DNKCIB FMBA" in 2019–2021. The diagnosis was confirmed using polymerase chain reaction method. Patient samples were also analyzed using culture-based methods. Total DNA was extracted using the QIAamp DNA Mini Kit. Genetic determinants encoding virulence factors and MLST typing were performed using the ResFinder program. The immune status of patients was assessed on days 1 and 7 of the illness. Immunological investigation included measurement of serum immunoglobulin concentrations (IgA, IgM, IgG), C-reactive protein, and cytokines (IL-1β, IL-1, IL-2, IL-4, IL-5, IL-6, IL- 7, IL-8, IL-10, TNF-α, and IFN-γ). Results. When analyzing the frequency of detection of Campylobacter sequence types in children with clinical intestinal infections, it was found that the profile of isolated isolates is most similar to those from countries of North America (USA and Canada), Northern Europe (Great Britain, Holland ) and Scandinavia (Denmark, Sweden, Finland). Identification of a pathogen with the flgE+, cdtA+, cdtC+ genotype was accompanied by a statistically significant increase in the level of IL-8 and a decrease in the content of IgA in the peripheral blood serum, which reflected the low efficiency of the immune response during infection with Campylobacter and predetermined the severe course of the infectious process during the disease.

Abstract Spatial distribution of intra-tumoral immune cell populations is considered a critical determinant of tumor evolution and response to therapy. The accurate and systemic search for contexture-based predictors would be accelerated by methods that allow interactive visualization and interrogation of tumor micro-environments (TME), independent of image acquisition platforms. To this end, we have developed the TME-Analyzer, a new image analysis tool, which we have benchmarked against 2 software tools regarding densities and networks of immune effector cells using multiplexed immune-fluorescent images of triple negative breast cancer (TNBC). With the TME-Analyzer we have identified a 10-parameter classifier, predominantly featuring cellular distances, that significantly predicted overall survival, and which was validated using multiplexed ion beam time of flight images from an independent cohort. In conclusion, the TME-Analyzer enabled accurate interactive analysis of the spatial immune phenotype from different imaging platforms as well as enhanced utility and aided the discovery of contextual predictors towards the survival of TNBC patients.

Abstract The ancestral sarbecovirus giving rise to SARS-CoV-2 is posited to have originated in bats. While SARS-CoV-2 causes asymptomatic to severe respiratory disease in humans, little is known about the biology, virus tropism, and immunity of SARS-CoV-2-like sarbecoviruses in bats. SARS-CoV-2 has been shown to infect multiple mammalian species, including various rodent species, non-human primates, and Egyptian fruit bats. We show that SARS-CoV-2 can utilize Jamaican fruit bat (Artibeus jamaicensis) ACE2 spike for entry in vitro. Therefore, we investigate the Jamaican fruit bat as a possible in vivo model to study reservoir responses. We find that SARS-CoV-2 Delta does not efficiently replicate in Jamaican fruit bats in vivo. We observe infectious viruses in the lungs of only one animal on day 1 post-inoculation and find no evidence of shedding or seroconversion. This is possibly due to host factors restricting virus egress after aborted replication. Furthermore, we observe no significant immune gene expression changes in the respiratory tract but do observe changes in the intestinal metabolome after inoculation. This suggests that, despite its broad host range, SARS-CoV-2 is unable to infect all bat species, and Jamaican fruit bats are not an appropriate model to study SARS-CoV-2 reservoir infection.

Abstract Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Clinical presentation and disease course are highly heterogeneous. Typically, disease progression occurs over time and is characterized by the gradual accumulation of disability. The risk of developing MS is driven by complex interactions between genetic and environmental factors, including the gut microbiome. How the commensal gut microbiota impacts disease severity and progression over time remains unknown. In a longitudinal study, disability status and associated clinical features in 58 MS patients were tracked over 4.2 ± 0.98 years, and the baseline fecal gut microbiome was characterized via 16S amplicon sequencing. Progressor status, defined as patients with an increase in Expanded Disability Status Scale (EDSS), were correlated with features of the gut microbiome to determine candidate microbiota associated with risk of MS disease progression. We found no overt differences in microbial community diversity and overall structure between MS patients exhibiting disease progression and non-progressors. However, a total of 41 bacterial species were associated with worsening disease, including a marked depletion in Akkermansia, Lachnospiraceae, and Oscillospiraceae, with an expansion of Alloprevotella, Prevotella-9, and Rhodospirillales. Analysis of the metabolic potential of the inferred metagenome from taxa associated with progression revealed enrichment in oxidative stress-inducing aerobic respiration at the expense of microbial vitamin K2 production (linked to Akkermansia), and a depletion in SCFA metabolism (linked to Oscillospiraceae). Further, as a proof of principle, statistical modeling demonstrated that microbiota composition and clinical features were sufficient to predict disease progression. Additionally, we found that constipation, a frequent gastrointestinal comorbidity among MS patients, exhibited a divergent microbial signature compared with progressor status. These results demonstrate a proof of principle for the utility of the gut microbiome for predicting disease progression in MS in a small well-defined cohort. Further, analysis of the inferred metagenome suggested that oxidative stress, vitamin K2, and SCFAs are associated with progression, warranting future functional validation and mechanistic study.

Background: The standard of care for unresectable locally advanced NSCLC is concurrent chemotherapy and radiation (CRT) followed by adjuvant durvalumab, established by the PACIFIC trial, which revealed acceptable although higher rates of pneumonitis with durvaluamb than placebo. We retrospectively reviewed patients with locally advanced NSCLC from 2018 to 2022 treated with definitive CRT (≥60 Gy) followed by at least one dose of adjuvant durvalumab. Objective: To review the incidence of pneumonitis and contributing factors, and also to review grade 5 pneumonitis (G5) events. Methods: We identified 78 cases with a median age of 70.0 years and a median follow-up of 36 months. All patients received CRT of at least 60 Gy at 2 Gy per fraction. A total of 22 patients (28.2%) completed 12 months of durvalumab. The cumulative incidence of any-grade pneumonitis was 28.2%. Pneumonitis rate in grades 1, 2, 3, 4, and 5 was 1.3%, 10.3%, 7.7%, 0.0%, and 9.0%, respectively. Results: Multivariate analysis did not reveal significant factors associated with G5 pneumonitis. There were 8 patients who received radiation therapy doses above standard limits and, of these, only two developed G5 pneumonitis. All patients with G5 pneumonitis had multiple comorbidities or previous malignancy treated with systemic therapy. The median overall survival was 31.1 months and the median progression-free survival was 12.7 months. Conclusions: We report comparable overall rates of pneumonitis relative to published data with higher rates of G5 pneumonitis. Patients with high-dose radiation therapy (≥60 Gy) and Eastern Cooperative Oncology Group performance status greater than or equal to 2 may tolerate adjuvant durvalumab, though providers should exercise caution in patients with extensive comorbidities.

Background: The challenging working conditions experienced by community health workers (CHWs) have an impact on their mental health, as detected by the NGO Compañeros En Salud (CES) in rural Mexico. In response to this situation, CES designed through a participatory process a package of interventions to promote the mental well-being of CHWs, beginning implementation in 2021. The objective of the present study was to learn how CES CHWs' work affects their mental well-being and to evaluate the intervention package to promote CHWs’ mental well-being implemented by CES. Methods: In June–August 2023, 52 CHWs from the CES-supported communities participated in the study, responding to a survey and participating in 10 focus group discussions. Quantitative data were analyzed using statistical descriptive analysis and qualitative data using thematic analysis. Findings: Participants highlighted the impact on their communities as one of the main aspects of their job that contribute positively to their mental well-being, as well as the challenging work-life balance as one of the main aspects that contribute negatively. As for the interventions, most participants considered them significant and positive for their mental well-being, highlighting positive aspects such as the possibility of creating community with their peers or a feeling of self-efficacy. However, the access to interventions was uneven among participants and most interventions presented areas for improvement, such as the periodicity of psychological distress screening or the response time to material needs. Conclusions: Efforts to support CHW well-being in the areas they signal as needs can impact their experiences around work and their perceived well-being. Access to work materials, preparedness on clinical topics, and relationships with their teams are key areas that may have a bearing on CHWs' emotional and mental well-being. Interventions aimed at these areas can positively impact CHWs’ self-efficacy, their community with each other, and their interactions with patients.

BackgroundMany patients do not receive a comprehensive medication reconciliation, mostly owing to limited resources. We hence need an approach to identify those patients at the emergency department (ED) who are at increased risk for clinically relevant discrepancies. ObjectiveThe aim of our study was to develop and externally validate a prediction model to identify patients at risk for at least 1 clinically relevant medication discrepancy upon ED presentation. MethodsA prospective, multicenter, observational study was conducted at the University Hospitals Leuven and General Hospital Sint-Jan Brugge-Oostende AV, Belgium. Medication histories were obtained from patients admitted to the ED between November 2017 and May 2022, and clinically relevant medication discrepancies were identified. Three distinct datasets were created for model development, temporal external validation, and geographic external validation. Multivariable logistic regression with backward stepwise selection was used to select the final model. The presence of at least 1 clinically relevant discrepancy was the dependent variable. The model was evaluated by measuring calibration, discrimination, classification, and net benefit. ResultsWe included 824, 350, and 119 patients in the development, temporal validation, and geographic validation dataset, respectively. The final model contained 8 predictors, for example, age, residence before admission, number of drugs, and number of drugs of certain drug classes based on Anatomical Therapeutic Chemical coding. Temporal validation showed excellent calibration with a slope of 1.09 and an intercept of 0.18. Discrimination was moderate with a c-index (concordance index) of 0.67 (95% CI 0.61-0.73). In the geographic validation dataset, the calibration slope and intercept were 1.35 and 0.83, respectively, and the c-index was 0.68 (95% CI 0.58-0.78). The model showed net benefit over a range of clinically reasonable threshold probabilities and outperformed other selection criteria. ConclusionsOur software-implemented prediction model shows moderate performance, outperforming random or typical selection criteria for medication reconciliation. Depending on available resources, the probability threshold can be customized to increase either the specificity or the sensitivity of the model.

Abstract Picophytoplankton are important primary producers, but not always adequately recognized, for example, due to methodological limitations. In this study, we combined flow cytometry and metabarcoding to investigate seasonal and spatial patterns of picophytoplankton abundance and community composition in the Elbe estuary. Due to the mixing of freshwater and seawater and the tidal currents this ecosystem is characterized by typical estuarine features such as salinity gradients and high turbidity. Picophytoplankton (mostly picoeukaryotes such as Mychonastes and Minidiscus) contributed on average 70% (SD = 14%) to the total phytoplankton counts. In summer picocyanobacteria (e.g., Synechococcus) played a more significant role. The contributions of picophytoplankton to the total phytoplankton were particularly high from summer to winter as well as in the mid estuary. However, at salinities of around 10 PSU in the mixing area of freshwater and seawater, the proportion of picophytoplankton was comparably low (average 49%, SD = 13%). Our results indicate that picophytoplankton prevail in the Elbe estuary year‐round with respect to cell counts. Picophytoplankton could occupy important niche positions to maintain primary production under extreme conditions where larger phytoplankton might struggle (e.g., at high or low temperature, high turbidity, and in areas with high grazing pressure) and also benefit from high nutrient availability here. However, we did not find evidence that they played a particularly significant role at the salinity interface. Our study highlights the importance of including picophytoplankton when assessing estuarine phytoplankton as has been suggested for other ecosystems such as oceans.

Abstract Escherichia coli A0 34/86 (EcO83) is a probiotic strain used in newborns to prevent nosocomial infections and diarrhoea. This bacterium stimulates both pro‐ and anti‐inflammatory cytokine production and its intranasal administration reduces allergic airway inflammation in mice. Despite its benefits, there are concerns about the use of live probiotic bacteria due to potential systemic infections and gene transfer. Extracellular vesicles (EVs) derived from EcO83 (EcO83‐EVs) might offer a safer alternative to live bacteria. This study characterizes EcO83‐EVs and investigates their interaction with host cells, highlighting their potential as postbiotic therapeutics. EcO83‐EVs were isolated, purified, and characterised following the Minimal Information of Studies of Extracellular Vesicles (MISEV) guidelines. Ex vivo studies conducted in human nasal epithelial cells showed that EcO83‐EVs increased the expression of proteins linked to oxidative stress and inflammation, indicating an effective interaction between EVs and the host cells. Further in vivo studies in mice demonstrated that EcO83‐EVs interact with nasal‐associated lymphoid tissue, are internalised by airway macrophages, and stimulate neutrophil recruitment in the lung. Mechanistically, EcO83‐EVs activate the NF‐κΒ signalling pathway, resulting in the nitric oxide production. EcO83‐EVs demonstrate significant potential as a postbiotic alternative to live bacteria, offering a safer option for therapeutic applications. Further research is required to explore their clinical use, particularly in mucosal vaccination and targeted immunotherapy strategies.

Self-regulatory and metacognitive instruction regarding student conceptions can help students become metacognitively (or more specifically, metaconceptually) aware of their conceptions and self-regulate their intuitive conceptions in scientific contexts when they are not appropriate. Two approaches have been found effective in enhancing conceptual knowledge: (a) self-assessing one’s conceptions and (b) acquiring conditional metaconceptual knowledge about why and in which contexts specific conceptions are appropriate or not. However, it is unclear how these approaches influence other cognitive and affective variables, such as self-efficacy and cognitive load. Nevertheless, it is essential to investigate whether making students aware of their intuitive conceptions affects their self-efficacy and to what extent reflecting on one’s conceptions requires additional (meta-)cognitive resources. Thus, we conducted an experimental intervention study using a 2×2 factorial design with N = 602 upper secondary biology students. Becoming metaconceptually aware of one’s (intuitive) conceptions did not lower students’ self-efficacy but enabled more accurate beliefs about their abilities. However, the self-assessment increased mental load, which partly suppressed the beneficial effect of the self-assessment on conceptual knowledge. In contrast, the instruction on conditional metaconceptual knowledge did not result in higher mental load and, thus, aligned more with students’ cognitive capacities. Furthermore, students with more pronounced general metaconceptual thinking reported lower mental load, implying that regular instruction focusing on metaconceptual thinking may reduce load. Thus, it is suggested to continuously promote students’ metaconceptual thinking and to embed metaconceptual activities (e.g., self-assessments) repeatedly across longer instructional units.

ObjectivesTo assess the reliability and validity of measuring resting cerebral blood flow (CBF) and hippocampal CBF using a single-post-labeling delay (PLD) and a multi-PLD pseudo-continuous arterial spin labeling (pCASL) protocol for cerebrovascular reactivity (CVR) testing.Methods25 healthy, midlife adults (57 ± 4 years old) were imaged in a Siemens Prisma 3T magnetic resonance imaging (MRI) scanner. Resting CBF and hippocampal CBF were assessed using two pCASL protocols, our modified single-PLD protocol (pCASL-MOD) to accommodate the needs for CVR testing and the multi-PLD Human Connectome Project (HCP) Lifespan protocol to serve as the reference control (pCASL-HCP). During pCASL-MOD, CVR was calculated as the change in CBF from rest to hypercapnia (+9 mmHg increase in end-tidal partial pressure of carbon dioxide [PETCO2]) and then normalized for PETCO2. The reliability and validity in resting gray matter (GM) CBF, white matter (WM) CBF, and hippocampal CBF between pCASL-MOD and pCASL-HCP protocols were examined using correlation analyses, paired t-tests, and Bland Altman plots.ResultsThe pCASL-MOD and pCASL-HCP protocols were significantly correlated for resting GM CBF [r = 0.72; F (1, 23) = 25.24, p < 0.0001], WM CBF [r = 0.57; F (1, 23) = 10.83, p = 0.003], and hippocampal CBF [r = 0.77; F (1, 23) = 32.65, p < 0.0001]. However, pCASL-MOD underestimated resting GM CBF (pCASL-MOD: 53.7 ± 11.1 v. pCASL-HCP: 69.1 ± 13.1 mL/100 g/min; p < 0.0001), WM CBF (pCASL-MOD: 32.4 ± 4.8 v. pCASL-HCP: 35.5 ± 6.9 mL/100 g/min; p = 0.01), and hippocampal CBF (pCASL-MOD: 50.5 ± 9.0 v. pCASL-HCP: 68.1 ± 12.5 mL/100 g/min; p < 0.0001). PETCO2 increased by 8.0 ± 0.7 mmHg to induce CVR (GM CBF: 4.8% ± 2.6%; WM CBF 2.9% ± 2.5%; and hippocampal CBF: 3.4% ± 3.8%).ConclusionOur single-PLD pCASL-MOD protocol reliably measured CBF and hippocampal CBF at rest given the significant correlation with the multi-PLD pCASL-HCP protocol. Despite the lower magnitude relative to pCASL-HCP, we recommend using our pCASL-MOD protocol for CVR testing in which an exact estimate of CBF is not required such as the assessment of relative change in CBF to hypercapnia.

Abstract Aims Current guidelines suggest calcium channel blockers (CCBs) as the second or third option for blood pressure management in patients with left ventricular assist device (LVAD). However, the clinical outcomes of patients with LVAD who receive CCBs remain unclear. Our study aims to analyse the association of CCBs with clinical outcomes in patients after LVAD implantation. Methods and results This is a retrospective analysis based on the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) from 2006 to 2017, and adult patients who were alive with LVAD and CCB treatment information at 6 months after implantation were included. Among 10 717 patients, 1369 received CCBs 6 months after implantation, and there was an increasing trend of CCB use after LVAD. Patients receiving CCB therapy at 6 months had a similar 5 year survival rate to those not receiving CCB [49.6%, 95% confidence interval (CI): 47.5–51.7% vs. 51.1%, 95% CI: 45.3–56.7%]. In both Cox and competing risk regressions after adjusting for confounding factors, CCB treatment at 6 months after implantation was not associated with long‐term mortality [hazard ratio (HR): 1.03, 95% CI: 0.91–1.17, P = 0.624 and subdistribution HR (SHR): 1.07, 95% CI: 0.95–1.22, P = 0.260]. Consistently, in time‐varying models, CCB treatment was not linked to long‐term mortality (HR: 0.97, 95% CI: 0.87–1.09, P = 0.682 and SHR: 1.05, 95% CI: 0.94–1.18, P = 0.359). This null association remained in subgroup analysis according to device strategy and propensity‐matching analyses. Neurological dysfunction, stroke, bleeding, rehospitalization, and renal dysfunction were more likely to occur among those with CCB when compared with those without CCB treatment. Conclusions In patients with LVAD, CCB therapy fails to show benefits in long‐term survival and is associated with increased incidences of neurological dysfunction, bleeding, renal dysfunction, and rehospitalization.

Abstract The global scientific response to COVID 19 highlighted the urgent need for increased throughput and capacity in bioanalytical laboratories, especially for the precise quantification of proteins that pertain to health and disease. Acoustic ejection mass spectrometry (AEMS) represents a much-needed paradigm shift for ultra-fast biomarker screening. Here, a quantitative AEMS assays is presented, employing peptide immunocapture to enrich (i) 10 acute phase response (APR) protein markers from plasma, and (ii) SARS-CoV-2 NCAP peptides from nasopharyngeal swabs. The APR proteins were quantified in 267 plasma samples, in triplicate in 4.8 h, with %CV from 4.2% to 10.5%. SARS-CoV-2 peptides were quantified in triplicate from 145 viral swabs in 10 min. This assay represents a 15-fold speed improvement over LC-MS, with instrument stability demonstrated across 10,000 peptide measurements. The combination of speed from AEMS and selectivity from peptide immunocapture enables ultra-high throughput, reproducible quantitative biomarker screening in very large cohorts.

Abstract People with lower extremity peripheral artery disease (PAD) have increased oxidative stress, impaired mitochondrial activity, and poor walking performance. NAD+ reduces oxidative stress and is an essential cofactor for mitochondrial respiration. Oral nicotinamide riboside (NR) increases bioavailability of NAD+ in humans. Among 90 people with PAD, this randomized double-blind clinical trial assessed whether 6-months of NR, with and without resveratrol, improves 6-min walk distance, compared to placebo, at 6-month follow-up. At 6-month follow-up, compared to placebo, NR significantly improved 6-min walk (+7.0 vs. −10.6 meters, between group difference: +17.6 (90% CI: + 1.8,+∞). Among participants who took at least 75% of study pills, compared to placebo, NR improved 6-min walk by 31.0 meters and NR + resveratrol improved 6-min walk by 26.9 meters. In this work, NR meaningfully improved 6-min walk, and resveratrol did not add benefit to NR alone in PAD. A larger clinical trial to confirm these findings is needed. Clinical Trials.gov registration: NCT03743636.

Abstract The erosion of the colonic mucus layer by a dietary fiber-deprived gut microbiota results in heightened susceptibility to an attaching and effacing pathogen, Citrobacter rodentium. Nevertheless, the questions of whether and how specific mucolytic bacteria aid in the increased pathogen susceptibility remain unexplored. Here, we leverage a functionally characterized, 14-member synthetic human microbiota in gnotobiotic mice to deduce which bacteria and functions are responsible for the pathogen susceptibility. Using strain dropouts of mucolytic bacteria from the community, we show that Akkermansia muciniphila renders the host more vulnerable to the mucosal pathogen during fiber deprivation. However, the presence of A. muciniphila reduces pathogen load on a fiber-sufficient diet, highlighting the context-dependent beneficial effects of this mucin specialist. The enhanced pathogen susceptibility is not owing to altered host immune or pathogen responses, but is driven by a combination of increased mucus penetrability and altered activities of A. muciniphila and other community members. Our study provides novel insights into the mechanisms of how discrete functional responses of the same mucolytic bacterium either resist or enhance enteric pathogen susceptibility.

Abstract Extracellular vesicles (EVs) are lipid-membrane enclosed structures that are associated with several diseases, including those of genitourinary tract. Urine contains EVs derived from urinary tract cells. Owing to its non-invasive collection, urine represents a promising source of biomarkers for genitourinary disorders, including cancer. The most used method for urinary EVs separation is differential ultracentrifugation (UC), but current protocols lead to a significant loss of EVs hampering its efficiency. Moreover, UC protocols are labor-intensive, further limiting clinical application. Herein, we sought to optimize an UC protocol, reducing the time spent and improving small EVs (SEVs) yield. By testing different ultracentrifugation times at 200,000g to pellet SEVs, we found that 48 min and 60 min enabled increased SEVs recovery compared to 25 min. A step for pelleting large EVs (LEVs) was also evaluated and compared with filtering of the urine supernatant. We found that urine supernatant filtering resulted in a 1.7-fold increase on SEVs recovery, whereas washing steps resulted in a 0.5 fold-decrease on SEVs yield. Globally, the optimized UC protocol was shown to be more time efficient, recovering higher numbers of SEVs than Exoquick-TC (EXO). Furthermore, the optimized UC protocol preserved RNA quality and quantity, while reducing SEVs separation time.

Abstract Lamotrigine is an effective mood stabiliser, largely used for the management and prevention of depression in bipolar disorder. The neuropsychological mechanisms by which lamotrigine acts to relieve symptoms as well as its neural effects on emotional processing remain unclear. The primary objective of this current study was to investigate the impact of an acute dose of lamotrigine on the neural response to a well-characterised fMRI task probing implicit emotional processing relevant to negative bias. 31 healthy participants were administered either a single dose of lamotrigine (300 mg, n = 14) or placebo (n = 17) in a randomized, double-blind design. Inside the 3 T MRI scanner, participants completed a covert emotional faces gender discrimination task. Brain activations showing significant group differences were identified using voxel-wise general linear model (GLM) nonparametric permutation testing, with threshold free cluster enhancement (TFCE) and a family wise error (FWE)-corrected cluster significance threshold of p

Freezing of gait (FOG) in Parkinson’s disease (PD) has a poorly understood pathophysiology, which hinders treatment development. Recent work showed a dysfunctional fronto-striato-limbic circuitry at rest in PD freezers compared to non-freezers in the dopamine “OFF” state. While other studies found that dopaminergic replacement therapy alters functional brain organization in PD, the specific effect of dopamine medication on fronto-striato-limbic functional connectivity in freezers remains unclear.

Abstract Adverse Outcome Pathways (AOPs) have been proposed to facilitate mechanistic understanding of interactions of chemicals/materials with biological systems. Each AOP starts with a molecular initiating event (MIE) and possibly ends with adverse outcome(s) (AOs) via a series of key events (KEs). So far, the interaction of engineered nanomaterials (ENMs) with biomolecules, biomembranes, cells, and biological structures, in general, is not yet fully elucidated. There is also a huge lack of information on which AOPs are ENMs-relevant or -specific, despite numerous published data on toxicological endpoints they trigger, such as oxidative stress and inflammation. We propose to integrate related data and knowledge recently collected. Our approach combines the annotation of nanomaterials and their MIEs with ontology annotation to demonstrate how we can then query AOPs and biological pathway information for these materials. We conclude that a FAIR (Findable, Accessible, Interoperable, Reusable) representation of the ENM-MIE knowledge simplifies integration with other knowledge. Scientific contribution This study introduces a new database linking nanomaterial stressors to the first known MIE or KE. Second, it presents a reproducible workflow to analyze and summarize this knowledge. Third, this work extends the use of semantic web technologies to the field of nanoinformatics and nanosafety.

Abstract Objectives The trial aimed to compare the clinical performance and radiographic success of ACTIVA BioACTIVE versus Compomer in restoring class-II cavities of primary molars. Materials and methods A non-inferior split-mouth design was considered. A pre-calculated sample size of 96 molars (48 per group) with class-2 cavities of twenty-one children whose ages ranged from 5 to 10 years were randomly included in the trial. Pre-operative Plaque Index (PI), DMFT/dmft scores and the time required to fill the cavity were recorded. Over 24 months, the teeth were clinically evaluated every six months and radiographically every 12 months by two calibrated and blinded evaluators using the United States public health service (USPHS)-Ryge criteria. The two-sided 95% confidence interval (CI) for the difference in success rate was considered to assess non-inferiority, and the margin was set at -18%. The linear mixed model and Firth’s logistic regression model were used for data analysis (P 0.05). ACTIVA took significantly less placement time than Dyract, with a mean difference of 2.37 (± 0.63) minutes (P

Abstract Objectives The Mental Health Inventory (MHI‐5) is frequently used as a screener for mood and anxiety disorders. However, few population‐based studies have validated it against a diagnostic instrument assessing disorders following current diagnostic criteria. Methods Within the third Netherlands Mental Health Survey and Incidence Study (NEMESIS‐3), a representative population‐based study of adults (N = 6194; age: 18–75 years), the MHI‐5 was used to measure general mental ill‐health in the past month. Presence of mood (major depressive disorder, persistent depressive disorder, or bipolar disorder) and anxiety disorders (panic disorder, agoraphobia, social phobia, or generalized anxiety disorder) in the past month was assessed with a slightly modified version of the Composite International Diagnostic Interview 3.0 per the Diagnostic and Statistical Manual of Mental disorders‐5. Results The MHI‐5 was good to excellent at distinguishing people with and without a mood disorder, an anxiety disorder, and any mood or anxiety disorder. The cut‐off value associated with the highest sensitivity and highest specificity for mood disorder was ≤68, and ≤76 for an anxiety disorder or any mood or anxiety disorder. Conclusions The MHI‐5 can identify individuals at high risk of a current mood or anxiety disorder in the general population when diagnostic interviews are too time consuming.

BackgroundTrust is a foundation of the therapeutic relationship and is associated with important patient outcomes. Building trust between parents of children with medical complexity (CMC) and physicians during inpatient care is complicated by lack of relational continuity, cumulative (sometimes negative) parent experiences and the need to adjust roles and expectations to accommodate parental expertise. This study's objective was to describe how parents of CMC conceptualize trust with physicians within the pediatric inpatient setting and to provide recommendations for building trust in these relationships.MethodsInterviews with 16 parents of CMC were completed and analyzed using interpretive description methodology.ResultsThe research team identified one overarching meta theme regarding factors that influence trust development: situational awareness is needed to inform personalized care of children and families. There were also six major themes: (1) ensuring that the focus is on the child and family, (2) respecting both parent and physician expertise, (3) collaborating effectively, (4) maintaining a flow of communication, (5) acknowledging the impact of personal attributes, and (6) recognizing issues related to the healthcare system.DiscussionMany elements that facilitated trust development were also components of patient- and family-centered care. Parents in this study approached trust with inpatient physicians as something that needs to be earned and reciprocated. To gain the trust of parents of CMC, inpatient physicians should personalize medical care to address the needs of each child and should explore the perceptions, expertise, and previous experiences of their parents.

Rationale Determining the ability of a country’s nursing workforce to meet the health care needs of the population is essential for optimal health outcomes. ‘Nursing shortage’ is frequently heralded as an issue, yet it is unclear how ‘shortage’ is defined and calculated. The purpose of this study was to collect and link publicly available Canadian data to describe and compare trends in nursing workforce capacity. Methods Primary data sources included linking Statistics Canada and Canadian Institutes of Health Information (CIHI) data from 2015 to 2022. Statistics Canada tracks provincial population data and job vacancy rates. CIHI receives data from provincial nursing organizations on demographics, roles, and employment status. To estimate a sufficient workforce, job vacancy rates (a proxy for provincial need) were cross tabulated with the number of registered nurses (RNs) and registered psychiatric nurses (RPNs) per year. Results The number of RNs and RPNs in Canada has increased by 8.6% between 2015 and 2022, to a total of 322,226. Job vacancies, as a percent of total nursing supply, shows a rising trend (2.3% to 8.7%) between 2015 and 2022 across Canada. In 2022, 84.9% of Canadian RNs and RPNs in direct patient care across Canada and 86.1% were in urban settings. Conclusion & Limitations This project examines Canadian nursing workforce data encompassing potential effects of the COVID-19 pandemic. The trends are limited to annual due to aggregated data. Data on a country’s nursing workforce measured monthly and consistently across provinces would yield clearer information.

ObjectiveVasoplegic syndrome remains a common complication of cardiac surgery. It has serious implications for the healthcare system and individual patients, as it leads to rising healthcare costs and higher mortality. A better understanding of factors triggering vasoplegic syndrome is essential for the development of effective prevention strategies. We aimed to identify clinical characteristics and intraoperative parameters associated with the development of vasoplegic syndrome in coronary artery bypass graft surgery and the influence of vasoplegia on outcome.MethodsWe retrospectively analyzed the data of all patients who underwent isolated coronary artery bypass graft surgery or coronary artery bypass graft surgery combined with atrial appendage occlusion, using the heart-lung machine at our institution from 04/2019 to 12/2020. Vasoplegic syndrome was defined as MAP ≤60 mmHg and norepinephrine equivalence dosage of ≥0.2 μg/kg/min with a central venous saturation ≥60% within 2 days from surgery.ResultsOf 647 patients included in this study, 72 (11.1%) developed vasoplegic syndrome. Patients experiencing vasoplegia had longer stay in ICU, more frequently underwent tracheostomy and suffered more often from pneumonia. The duration of extracorporeal circulation, intraoperative application of platelet concentrates and usage of cold crystalloid cardioplegia (Bretschneider) independently predicted development of vasoplegic syndrome.ConclusionsEven in relatively low-risk cardiac surgery, vasoplegic syndrome is a common complication and was associated with serious adverse effects. The use of warm blood cardioplegia (Calafiore) seems to be safer than cold crystalloid cardioplegia (Bretschneider) and might be preferable in patients that are vulnerable to the consequences of vasoplegic syndrome.

ABSTRACT: Background: Pain, disability and progressive kyphosis is a common problem after traumatic injury of the thoracolumbar (TL-) junction. Surgical treatment may include long-segment posterior or short-segment anterior-posterior fusion. We aim to report our experience with the application of short-segment posterior instrumented fusion with anterior column support using lateral lumbar or thoracic interbody (LLIF) cages. Methods: In this retrospective, single-center observational cohort study we included consecutive patients treated surgically for traumatic injury of the TL-junction (Th10/11-L2/3) by posterior instrumentation/fusion and LLIF. We measured segmental kyphosis, complications, and outcomes until last follow-up (about 3 years postoperative). Results: We identified 61 patients (mean age 39.0 years [SD 13.3]; 23 females [37.7%]) with A3 fractures without (n=48; 78.7%) or with additional sagittal split component n=11; 18.0%. Additional posterior tension band injury was present in n=26 (42.6%). The affected levels of injury were Th12/L1 in n=25 (41.0%) and Th11/12 in n=22 (36.1%). The segmental kyphotic angle was 14.6° (6.7°) preoperative and remained significantly reduced at all times of follow-up at discharge (5.4°±5.5°; p

ABSTRACT: Background: Transforaminal anterior release (TFAR) is a technical extension of the transforaminal lumbar interbody fusion (TLIF) procedure with deliberate release of the anterior longitudinal ligament (ALL). Methods: In a retrospective, single-center observational cohort study, consecutive adult patients undergoing TLIF surgery at L4/L5 and/or L5/S1 between 01/2018 and 12/2022 for degenerative disc disease or deformity were considered. The TFAR group (with ALL release) was compared to a standard TLIF group (without ALL release), matched in a 1:3 ratio. Uni- and multivariable logistic regression models were built to estimate the likelihood of any adverse event (AE), reoperation, and excellent/good clinical outcome at 12 months. Results: Of 438 patients, 18 undergoing TFAR were matched to 53 undergoing standard TLIF. TFAR procedures were frequently part of extensive, anterior-posterior or multilevel fusion procedures with longer surgery time and higher blood loss. The rates of intraoperative surgical AEs were similar (16.7 vs. 11.3%, p=.789). The rates and severities of surgical AEs, as well as reoperation rates and clinical outcomes were similar at time of discharge, 90 days, and 12 months postoperatively (all p>.05). TFAR allowed for an increase in total lumbar lordosis of 16.1° and in lumbar lordosis between L4 and S1 of 16.3° at discharge, which was maintained during follow-up. In both the uni- and multivariable models, patients undergoing TFAR were as likely as patients undergoing standard TLIF to experience any AE (adjusted OR 0.78, 95% CI 0.21–2.94), any reoperation (aOR 0.46, 95% CI 0.11–1.90) or excellent/good clinical outcome at 12 months (aOR 2.01, 95% CI 0.52–7.74). Conclusions: The TFAR technique has a safety profile which is comparable to the standard TLIF procedure, but it allows for a greater restoration of lumbar lordosis at L4-S1. We suggest considering the TFAR technique in selected patients with sagittal imbalance and mobile segments for restoration of lumbar lordosis.

Summary: Trained immunity is characterized by histone modifications and metabolic changes in innate immune cells following exposure to inflammatory signals, leading to heightened responsiveness to secondary stimuli. Although our understanding of the molecular regulation of trained immunity has increased, the role of adaptive immune cells herein remains largely unknown. Here, we show that T cells modulate trained immunity via cluster of differentiation 40-tissue necrosis factor receptor-associated factor 6 (CD40-TRAF6) signaling. CD40-TRAF6 inhibition modulates functional, transcriptomic, and metabolic reprogramming and modifies histone 3 lysine 4 trimethylation associated with trained immunity. Besides in vitro studies, we reveal that single-nucleotide polymorphisms in the proximity of CD40 are linked to trained immunity responses in vivo and that combining CD40-TRAF6 inhibition with cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4-Ig)-mediated co-stimulatory blockade induces long-term graft acceptance in a murine heart transplantation model. Combined, our results reveal that trained immunity is modulated by CD40-TRAF6 signaling between myeloid and adaptive immune cells and that this can be leveraged for therapeutic purposes.

ABSTRACT Symbiotic interactions between humans and our communities of resident gut microbes (microbiota) play many roles in health and disease. Some gut bacteria utilize mucus as a nutrient source and can under certain conditions damage the protective barrier it forms, increasing disease susceptibility. We investigated how Ruminococcus torques—a known mucin degrader that has been implicated in inflammatory bowel diseases (IBDs)—degrades mucin glycoproteins or their component O-linked glycans to understand its effects on the availability of mucin-derived nutrients for other bacteria. We found that R. torques utilizes both mucin glycoproteins and released oligosaccharides from gastric and colonic mucins, degrading these substrates with a panoply of mostly constitutively expressed, secreted enzymes. Investigation of mucin oligosaccharide degradation by R. torques revealed strong α-L-fucosidase, sialidase and β1,4-galactosidase activities. There was a lack of detectable sulfatase and weak β1,3-galactosidase degradation, resulting in accumulation of glycans containing these structures on mucin polypeptides. While the Gram-negative symbiont, Bacteroides thetaiotaomicron grows poorly on mucin glycoproteins, we demonstrate a clear ability of R. torques to liberate products from mucins, making them accessible to B. thetaiotaomicron. This work underscores the diversity of mucin-degrading mechanisms in different bacterial species and the probability that some species are contingent on others for the ability to more fully access mucin-derived nutrients. The ability of R. torques to directly degrade a variety of mucin and mucin glycan structures and unlock released glycans for other species suggests that it is a keystone mucin degrader, which might contribute to its association with IBD.IMPORTANCEAn important facet of maintaining healthy symbiosis between host and intestinal microbes is the mucus layer, the first defense protecting the epithelium from lumenal bacteria. Some gut bacteria degrade the various components of intestinal mucins, but detailed mechanisms used by different species are still emerging. It is imperative to understand these mechanisms as they likely dictate interspecies interactions and may illuminate species associated with bacterial mucus damage and subsequent disease susceptibility. Ruminococcus torques is positively associated with IBD in multiple studies. We identified mucin glycan-degrading enzymes in R. torques and found that it shares mucin degradation products with another species of gut bacteria, Bacteroides thetaiotaomicron. Our findings underscore the importance of understanding mucin degradation mechanisms in different gut bacteria and their consequences on interspecies interactions, which may identify keystone bacteria that disproportionately affect mucus damage and could therefore be key players in effects that result from reductions in mucus integrity.