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Background: Cardiac rehabilitation programs provide a valuable opportunity to promote the adoption of healthy lifestyle behaviors in patients with atherosclerotic cardiovascular diseases (ASCVDs) and metabolic comorbidities, including metabolic syndrome and prediabetes. However, strategies to reverse these conditions remain to be explored. The DIABEPIC-1 study aimed to assess the feasibility of an enhanced 6-month cardiac rehabilitation program for patients with ASCVD while investigating prediabetes and metabolic syndrome remission. Methods: The study combined exercise training with a comprehensive nutritional intervention, emphasizing reduction in intake of ultraprocessed foods, adoption of a Mediterranean diet, and implementation of time-restricted eating. Baseline, 3-month, and 6-month assessments included segmental body-composition measurements, blood analysis, maximal exercise testing, nutritional diaries recorded with the Keenoa AI app, and lifestyle questionnaires. Remission criteria included a return to an HbA1c level of < 5.7%, and < 3 National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP-III) criteria for prediabetes and metabolic syndrome, respectively. Results: A total of 36 participants were recruited. The study demonstrated completion rates of 94.4% at 3 months, and 88.9% at 6 months, and a mean compliance rate of 92.5% for planned clinical appointments. Significant reductions in waist circumference (–9.2 cm, P < 0.001) and weight (–8.0 kg, P < 0.001) were observed. Improvement in glycemic and lipid profiles, insulin-resistance marker levels, and liver health were noted. Participants enhanced their cardiorespiratory fitness, reduced their consumption of ultraprocessed food, and increased their adherence to the Mediterranean diet and time-restricted eating. Notably, 50% achieved prediabetes remission, and 70% with metabolic syndrome at baseline achieved remission. Conclusions: The study demonstrates the possibility of enhancing cardiac rehabilitation with an intensive nutritional intervention, yielding clinically significant outcomes, including remission of key risk factors in a substantial number of ASCVD patients. Clinical Trial Registration: ClinicalTrials.gov, NCT05459987. Résumé: Contexte: Les programmes de réadaptation cardiaque offrent une occasion précieuse de promouvoir l'adoption d'un mode de vie sain chez les patients atteints de maladies cardiovasculaires athéroscléreuses (MCVA) et de comorbidités métaboliques, notamment le syndrome métabolique et le prédiabète. Cependant, les stratégies visant à inverser ces conditions restent à explorer. L'étude DIABEPIC-1 visait à évaluer la faisabilité d'un programme de réadaptation cardiaque renforcé de 6 mois pour les patients atteints de MCVA tout en examinant la rémission du prédiabète et du syndrome métabolique. Méthodes: L'étude a combiné un entraînement physique avec une intervention nutritionnelle complète, mettant l'accent sur la réduction de la consommation d'aliments ultra-transformés, l'adoption d'un régime méditerranéen et la mise en œuvre d'une alimentation restreinte dans le temps. Les évaluations de base, à 3 mois et à 6 mois, comprenaient des mesures de la composition corporelle par segments, des analyses sanguines, des tests d'exercice maximal, la tenue de journaux nutritionnels enregistrés avec l'application Keenoa AI et des questionnaires sur le mode de vie. Les critères de rémission comprenaient un retour à un niveau d'hémoglobine glyquée HbA1c < 5,7 %, et < 3 critères de la table du « National Cholesterol Education Program Adult Treatment Panel III » (NCEP/ATP-III) pour le prédiabète et le syndrome métabolique, respectivement. Résultats: Au total, 36 participants ont été recrutés. L'étude a montré des taux d'achèvement de 94,4 % à 3 mois et de 88,9 % à 6 mois, ainsi qu'un taux de conformité moyen de 92,5 % pour les rendez-vous cliniques planifiés. Des réductions significatives du tour de taille (-9,2 cm, p < 0,001) et du poids (-8,0 kg, p < 0,001) ont été observées. Une amélioration des profils glycémiques et lipidiques, des niveaux de marqueurs de résistance à l'insuline et de la santé hépatique a été constatée. Les participants ont amélioré leur condition cardiorespiratoire, réduit leur consommation d'aliments ultra-transformés et augmenté leur adhésion au régime méditerranéen et à l'alimentation restreinte dans le temps. Notamment, 50 % des participants ont obtenu une rémission du prédiabète et 70 % des participants atteints du syndrome métabolique au début de l'étude ont atteint la rémission. Conclusions: L'étude démontre la possibilité d'améliorer la réadaptation cardiaque par une intervention nutritionnelle intensive, produisant des résultats cliniquement significatifs, y compris la rémission des principaux facteurs de risque chez un nombre substantiel de patients atteints de MCVA. Enregistrement de l'essai clinique: ClinicalTrials.gov, NCT05459987.

Floodplains are unique environments that provide a dynamic link between terrestrial and aquatic systems. Intensification of human activity – particularly agriculture and urbanisation – has resulted in the degradation of floodplains worldwide. Restoration and sustainable management of floodplains requires holistic assessment and compromise between stakeholders to successfully balance environmental, economic, and social benefits. Yet, understanding these complex systems sufficiently to provide evidence-based recommendations is a challenge. We present the lessons learned from establishing an interdisciplinary research-based framework on the agricultural floodplain of Lake Saint Pierre, Québec, Canada, whose mandate was to a) understand and define key environmental, agricultural, and socioeconomic attributes of the landscape, b) quantify the trade-offs and synergies between these attributes across different agricultural practices, regions, and land uses, and c) explore novel agri-environmental management practices to assess their role in sustainable floodplain management. Within this manuscript, we explore the benefits that such an approach offers in evaluating sustainable floodplain land use. We found that an interdisciplinary research-based approach demonstrated important benefits such as knowledge transfer, more efficient use of resources (e.g., personnel, funding), and a flexible yet robust research framework. A framework of individual research projects connected to broader interdisciplinary themes allowed a more holistic synthesis of the floodplain systems and assessment of agri-environmental practices. By implicitly considering spatial and social scales, we conceptualised not just how redistribution of the land use types can meet sustainable management objectives, but also explored how compromises within existing uses can optimise socio-economic, agricultural and environmental dimensions and move towards a sustainable multifunctional landscape.

Ependymomas are rare nervous system tumors that can arise anywhere in the neuraxis. While having a high propensity for leptomeningeal dissemination, retrograde dissemination (from the spine to the CNS) remains infrequent. We describe the case of a 31-year-old female who presented with hydrocephalus secondary to an intracranial leptomeningeal metastasis of a giant spinal ependymoma with mixed (classic and myxopapillary) histopathologic features, successfully treated with surgical resection and radiotherapy of the entire neuraxis. This case highlights the importance of including ependymomas in the differential diagnosis for lesions in atypical extra-axial locations, of systematically obtaining imaging of the entire neuraxis when suspecting it, and of considering retrograde dissemination when both intracranial and spinal lesions are present.

Background: Increased gray matter volume (GMV) following electroconvulsive therapy (ECT) has been well-documented, with limited studies reporting a subsequent decrease in GMV afterwards. Objective: This study characterized the reversion pattern of GMV after ECT and its association with clinical depression outcome, using multi-site triple time-point data from the Global ECT-MRI Research Collaboration (GEMRIC). Methods: 86 subjects from the GEMRIC database were included, and GMV in 84 regions-of-interest (ROI) was obtained from automatic segmentation of T1 MRI images at three timepoints: pre-ECT (T0), within one-week post-ECT (T1), and one to six months post-ECT (T2). RM-ANOVAs were used to assess longitudinal changes and LMM analyses explored associations between GMV changes and demographical and clinical characteristics. Results: 63 of the 84 ROIs showed a significant increase-and-decrease pattern (RM-ANOVA, Bonferroni corrected p

The distribution of fiber diameters plays a crucial role in the transport and sound absorbing properties of a three-dimensional random fibrous (3D-RF) medium. Conventionally, volume-weighted averaging of fiber diameters has been utilized as an appropriate microstructural descriptor to predict the static viscous permeability of 3D-RF media. However, the long wavelength acoustical properties of a 3D-RF medium are also sensitive to the smallest fibers, this is particularly true in the high-frequency regime. In our recent research, we demonstrated that an inverse volume-weighted averaging of fiber diameters can effectively serve as a complementary microstructural descriptor to capture the high-frequency behavior of polydisperse fibrous media. In the present work, we reexamine the identification of two representative volume elements (RVEs) which relies on the reconstruction of 3D-RF microstructures having volume-weighted and inverse-volume weighted averaged fiber diameters, respectively in the low-frequency and high frequency regimes. We investigate the implication of such a weighting procedure on the transport and sound absorbing properties of polydisperse fibrous media, highlighting their potential advantages. Furthermore, we discuss the challenges associated with this research field. Finally, we provide a brief perspective of the future directions and opportunities for advancing this area of study.

Summary: Background: We apply endoscopic ultrasound-guided fine needle aspiration biopsy to cytopathologically diagnose and sample nucleic acids from primary tumours regardless of the disease stage. Methods: 397 patients with proven pancreatic adenocarcinoma were included and followed up in a multicentre prospective study. DNA and mRNA were extracted from materials of primary tumours obtained by endoscopic ultrasound-guided fine needle aspiration biopsy and analysed using targeted deep sequencing and RNAseq respectively. Findings: The variant allele frequency of the KRAS mutation was used to evaluate the tumour cellularity, ranging from 15 to 20% in all cells, regardless of the tumour stage. The molecular profile of metastatic primary tumours significantly differed from other types of tumours, more frequently having TP53 mutations (p = 0.0002), less frequently having RNF43 mutations, and possessing more basal-like mRNA component (p = 0.001). Molecular markers associated with improved overall survival were: mutations in homologous recombination deficiency genes in patients who received first-line platinum-based chemotherapy (p = 0.025) and wild-type TP53 gene in patients with locally advanced tumours who received radio-chemotherapy (p = 0.01). The GemPred transcriptomic profile was associated with a significantly better overall survival in patients with locally advanced or metastatic pancreatic cancer who received a gemcitabine-based first-line treatment (p = 0.019). Interpretation: The combination of genomic and transcriptomic analyses of primary pancreatic tumours enables us to distinguish metastatic tumours from other tumour types. Our molecular strategy may assist in predicting overall survival outcomes for platinum or gemcitabine-based chemotherapies, as well as radio-chemotherapy. Funding: Institut National Du Cancer (BCB INCa_7294), CHU of Toulouse, Inserm and Ligue Nationale Contre le Cancer (CIT program).

Summary: Background: Individuals with type 1 diabetes (T1D) are traditionally perceived as lean, but recent evidence suggests an increasing trend of obesity. To provide global estimates, this study explored the prevalence of obesity among adults with and without T1D across three distinct global regions. Methods: An observational, cross-sectional study was performed utilizing data from T1D registries and national health surveys to assess the prevalence of obesity (BMI ≥ 30 kg/m2) and the prevalence of overweight and obesity (BMI ≥ 25 kg/m2) across Belgium, Kuwait, and Mexico. Demographic and clinical characteristics of adults with and without T1D were assessed. Prevalence estimates were calculated through a binomial generalized linear mixed-effects model adjusting for age, sex, HbA1c, and survey year. As a sensitivity analysis, propensity score matching was performed for confounder adjustment of age and sex. Findings: The study encompassed 3594 individuals with T1D (from 2003 to 2022) and 9898 without T1D (from 2014 to 2021). After model adjustment for confounders (age, sex, HbA1c% and data-collection year), individual obesity prevalence was lower in individuals with T1D in Kuwait and Mexico than among those without type 1 diabetes (Kuwait: 22% (CI: 18–26%) vs. 44% (CI: 41–48%); Mexico: 5% (CI: 3–7%) vs. 40% (CI: 38–42%)). In contrast, individuals with T1D in Belgium showed a more comparable proportions to those without T1D (12% (CI: 9–16%) vs. 16% (CI:11–22%)). Interpretation: Our data reveal that obesity is prevalent among people with T1D. These findings underscore the need for targeted strategies in T1D care that address the growing concern of obesity. Funding: This manuscript is part of the Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy (SOPHIA) project (www.imisophia.eu). SOPHIA has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 875534. This Joint Undertaking support from the European Union’s Horizon 2020 research and innovation program and EFPIA and type 1 diabetes Exchange, Breakthrough T1D, and Obesity Action Coalition.

Summary: Background: Clinical severity scores can identify patients at risk of severe disease and death, and improve patient management. The modified early warning score (MEWS), the quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA), and the Universal Vital Assessment (UVA) were developed as risk-stratification tools, but they have not been fully validated in low-resource settings where fever and infectious diseases are frequent reasons for health care seeking. We assessed the performance of MEWS, qSOFA, and UVA in predicting mortality among febrile patients in the Lao PDR, Malawi, Mozambique, and Zimbabwe. Methods: We prospectively enrolled in- and outpatients aged ≥ 15 years who presented with fever (≥37.5 °C) from June 2018–March 2021. We collected clinical data to calculate each severity score. The primary outcome was mortality 28 days after enrolment. The predictive performance of each score was determined using area under the receiver operating curve (AUC). Findings: A total of 2797 participants were included in this analysis. The median (IQR) age was 32 (24–43) years, 38% were inpatients, and 60% (1684/2797) were female. By the time of follow-up, 7% (185/2797) had died. The AUC (95% CI) for MEWS, qSOFA and UVA were 0.67 (0.63–0.71), 0.68 (0.64–0.72), and 0.82 (0.79–0.85), respectively. The AUC comparison found UVA outperformed both MEWS (p

An increasingly common practice for policy-makers is to leverage e-participation to collect citizens’ opinions and improve their decision-making processes. This practice, however, is hindered by the large quantity of collected opinions which are often overloading and hard to value. This is referred to as information overload. As a way to mitigate this challenge for policy-makers, this article develops a prioritization framework for citizens’ ideas collected through e-participation. The framework builds on Design Science Research and is validated on a real-world case in collaboration with the European Commission. The resulting contributions are threefold. First, theoretical criteria, popularity and polarization, are developed to prioritize citizens’ proposals. Then, automated and quantitative metrics are proposed to measure these criteria. Finally, a prioritization matrix is developed to visually assess the relative priority of these citizens’ proposals.

Background: Social distancing restrictions during the COVID-19 pandemic caused disruptions to sexual health services (SHS) worldwide. During the first year of the pandemic, Lebanon implemented multiple lockdowns during which SHS endured repetitive closures. We explore the impact of the pandemic on SHS delivery and the diagnosis rate of sexually transmitted infections (STIs) among attendees of a large sexual health clinic in Beirut, Lebanon. Methods: This was a retrospective analysis of the clinic's database, including data on voluntary counseling and testing (VCT) for HIV, syphilis, hepatitis B virus (HBV), and hepatitis C virus (HCV). We compared the number and types of services provided, and the number and rate of positive VCT diagnoses pre- (Mar 2019–Feb 2020) and post- (Mar 2020–Feb 2021) COVID-19 onset. Results: Men who have sex with men (MSM) comprised 35 % and 40 % of attendees pre- and post- COVID-19 onset, respectively. Post-COVID-19 onset, a total of 1350 VCT services and 406 medical consultations were provided, an overall 45 % decrease compared with pre-COVID-19 onset. The prevalence pre-COVID-19 onset of HIV, syphilis, HBV, and HCV was 0.8 %, 0.3 %, 0.2 %, and 0.1 %, respectively, and post-COVID-19 onset 1.2 %, 0.7 %, 0.3 %, and 0.3 %, respectively. Post-COVID-19 onset, 1.7 % of patients tested positive for any STI compared with 1.1 % pre-COVID-19 onset (OR: 1.5, 95%CI: 0.8–2.7). Close to 90 % of all positive diagnoses were among MSM. The prevalence of HIV, syphilis, HBV, and HCV among MSM in the total sample was 2.1 %, 1.2 %, 0.4 %, and 0.3 %, respectively. Conclusion: COVID-19 related closures led to substantial reduction in SHS accessibility among clinic attendees. STI positivity rates increased post-COVID-19 onset, although this increase was not statistically significant. Findings suggest that sexual risk behavior was taking place during the pandemic despite the lockdowns and highlight the need to minimize disruptions in provision of SHS during similar crises, particularly to key populations.

Purpose: Radiation therapy (RT) exerts its anti-tumour efficacy by inducing direct damage to cancer cells but also through modification of the tumour microenvironment (TME) by inducing immunogenic antitumor response. Conversely, RT also promotes an immunosuppressive TME notably through the recruitment of regulatory T cells (Tregs). Glycoprotein A repetitions predominant (GARP), a transmembrane protein highly expressed by activated Tregs, plays a key role in the activation of TGF-β and thus promotes the immunosuppressive action of Tregs. The development of a theranostic approach targeting GARP combining imaging and targeted radionuclide therapy (TRT) was carried out. Methods: A preclinical model of 4T1 triple negative breast tumour-bearing BALB/c mice was used to show that GARP expression is increased after external beam radiation in the TME of our cancer model. We generated a theranostic probe through the bioconjugation of the chelating agent DOTAGA onto an anti-GARP monoclonal antibody. The bioconjugation with DOTAGA allows the radiolabelling of the DOTAGA-GARP conjugate with both Indium-111 for SPECT imaging and Lutetium-177 for TRT purposes. Results: We demonstrate that GARP expression is increased following RT in vivo and can be specifically detected and quantified using in vivo SPECT imaging with [111In]In-DOTAGA-GARP. In addition, 177Lu-DOTAGA-GARP limits tumour growth in our cancer model. Conclusion: This theranostic strategy may allow for the personalization of cancer treatments by early detection of activated Tregs infiltration following RT and identification of patients likely to respond to Tregs-targeted therapy via TRT.

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

Postoperative infections are the most common complications faced by surgeons after implant surgery. To address this issue, an emerging and promising approach is to develop antimicrobial coatings using antibiotic substitutes. We investigated the use of polycationic homopolypeptides in a layer-by-layer coating combined with hyaluronic acid (HA) to produce an effective antimicrobial shield. The three peptide-based polycations used to make the coatings, poly(l-arginine) (PAR), poly(l-lysine), and poly(l-ornithine), provided an efficient antibacterial barrier by a contact-killing mechanism against Gram-positive, Gram-negative, and antibiotic-resistant bacteria. Moreover, this activity was higher for homopolypeptides containing 30 amino-acid residues per polycation chain, emphasizing the impact of the polycation chain length and its mobility in the coatings to deploy its contact-killing antimicrobial properties. However, the PAR-containing coating emerged as the best candidate among the three selected polycations, as it promoted cell adhesion and epithelial monolayer formation. It also stimulated nitric oxide production in endothelial cells, thereby facilitating angiogenesis and subsequent tissue regeneration. More interestingly, bacteria did not develop a resistance to PAR and (PAR/HA) also inhibited the proliferation of eukaryotic pathogens, such as yeasts. Furthermore, in vivo investigations on a (PAR/HA)-coated hernia mesh implanted on a rabbit model confirmed that the coating had antibacterial properties without causing chronic inflammation. These impressive synergistic activities highlight the strong potential of PAR/HA coatings as a key tool in combating bacteria, including those resistant to conventional antibiotics and associated to medical devices.

Summary: Background: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. Methods: Exposure–response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. Findings: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13–15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13–15 and positive CT (1.21–2.81), GCS 9–12 (1.16–2.02), GCS 3–8 (1.09–1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51–1.80) percentages of unfavourable outcome were 37–51% in the lowest quintiles of biomarker levels and reached 90–94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83–3.79), the percentages were 2–4% and 19–28% in the lowest and highest biomarker quintiles, respectively. Interpretation: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. Funding: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.

Quantifying the pre-season workload of professional Rugby Union players, in relation to their respective positions not only provides crucial insights into their physical demands and training needs but also underscores the significance of the acute:chronic workload ratio (ACWR) in assessing workload. However, given the diversity in ACWR calculation methods, their applicability requires further exploration. As a result, this study aims to analyze the workload depending on the player's positions and to compare three ACWR calculation methods. Fifty-seven players were categorized into five groups based on their playing positions: tight five (T5), third-row (3R), number nine (N9), center, and third line defense (3L). The coupled and uncoupled rolling averages (RA), as well as the exponentially weighted moving average ACWR method, were employed to compute measures derived from GPS data. Changes throughout the pre-season were assessed using the one-way and two-way analysis of variance. The results revealed that N9 covered significantly greater distances and exhibited higher player load compared to T5 and 3L [p 2.5 m s−2), accelerations (>2.5 m s−2), acceleration distance (>2 m s−2), high-speed running (>15 km h−1), very high-speed running (>21 km h−1, VSHR), sprint running (>25 km h−1, SR) distance. When using coupled RA ACWR method, centers exposed significantly greater values to T5 (p

The emergence of the severe acute respiratory syndrome 2 (SARS-CoV-2) as a global threat has driven the urgent need for the identification of bioactive molecules capable of controlling or completely eradicating this virus. Our group has been investigating isatin hybrids that block the binding of the human angiotensin-converting enzyme 2 (ACE2) and the viral spike protein. This work describes the synthesis and biological evaluation of two derivatives of isatin (indol-2,3-dione) based on a computational approach. Isatin, a secondary metabolite of tryptophan, has been used as the core structure and is a versatile and favorable precursor and as a privileged scaffold against this enzyme complex. The new compound scaffolds AVS-01 and AVS-02 were designed by modifications at the C-3 and N-1 positions, respectively, according to the various reagents available in our lab. Molecular docking of the designed compounds was used to explore their interactions with the target protein complex. The two designed compound scaffolds shown in this article showed quite distinct docking glide scores (GScore = −3.657 and −4.534 for AVS-01 and AVS-02, respectively). Several analogs were synthesized and tested in the quest to find a plausible scaffold for further synthesis. While compound AVS-02 showed inhibition of spike/ACE2 binding with an IC50 value of 8.8 µM, the reference compound hopeaphenol inhibited the interaction with an IC50 of 0.3 µM. Compound AVS-01 rather showed no inhibition of the SARS-CoV-2 spike/host ACE2 interaction with an IC50 > 32 µM. An estimation of their binding free energy (ΔGbind), and free energy of solvation (ΔGsolv) MM-GBSA calculations was carried out to re-evaluate the affinity to the target protein to gain further insights into the observed activity and non-activity. MM-GBSA calculation showed that ΔGbind = −35.91 kcal/mol and-25.32 kcal/mol for AVS-01 and AVS-02, respectively, and ΔGsolv = 25.56 kcal/mol and 16.92 kcal/mol for AVS-01 and AVS-02, respectively. This leads to the conclusion that the N-1 position of the indole-2,3-dione moiety favors the blockage of SARS-CoV-2 spike/ACE2 interactions compared to the C-3 position. Analysis of GScores, per-residue interaction energies, and free energies of binding and solvation showed that van der Waals interactions should favor the binding towards the spike/ACE2 complex.

Silicon technology offers the enticing opportunity for monolithic integration of quantum and classical electronic circuits. However, the power consumption levels of classical electronics may compromise the local chip temperature and hence affect the fidelity of qubit operations. In the current work, a quantum-dot-based thermometer embedded in an industry-standard silicon field-effect transistor (FET) was adopted to assess the local temperature increase produced by an active FET placed in close proximity. The impact of both static and dynamic operation regimes was thoroughly investigated. When the FET was operated statically, a power budget of 45 nW at 100-nm separation was found, whereas at 216 μm, the power budget was raised to 150 μW. Negligible temperature increase for the switch frequencies tested up to 10 MHz was observed when operating dynamically. The current work introduced a method to accurately map out the available power budget at a distance from a solid-state quantum processor, and indicated the possible conditions under which cryoelectronics circuits may allow the operation of hybrid quantum–classical systems.

Summary: Background: Canadian Arctic communities have experienced sustained syphilis transmission, with diagnoses rates 18-times higher than the national average. Remoteness from laboratory facilities leads to delays between syphilis screening and treatment, contributing to onward transmission. Rapid diagnostic tests can eliminate treatment delays via testing at the point-of-care. This study aims to describe syphilis diagnostic gaps and to estimate the impact of introducing rapid diagnostic tests at the point-of-care on syphilis transmission. Methods: To assess the population-level impact of deploying rapid diagnostic tests, an individual-based model was developed using detailed surveillance data, population surveys, and a prospective diagnostic accuracy field study. The model was calibrated to syphilis diagnoses (2017–2022) from a community of approximately 1,050 sexually active individuals. The impacts of implementing rapid diagnostic tests using whole blood (sensitivity: 92% for infectious and 81% for non-infectious syphilis; specificity: 99%) from 2023 onward was calculated using the annual median fraction of cumulative new syphilis infections averted over 2023–2032. Findings: The median modeled syphilis incidence among sexually active individuals was 44 per 1,000 in 2023. Males aged 16–30 years exhibited a 51% lower testing rate than that of their female counterparts. Maintaining all interventions constant at their 2022 levels, implementing rapid diagnostic tests could avert a cumulative 33% (90% credible intervals: 18–43%) and 37% (21–46%) of new syphilis infections over 5 and 10 years, respectively. Increasing testing rates and contact tracing may enhance the effect of rapid diagnostic tests. Interpretation: Implementing rapid diagnostic tests for syphilis in Arctic communities could reduce infections and enhance control of epidemics. Such effective diagnostic tools could enable rapid outbreak responses by providing same-day testing and treatment at the point-of-care. Funding: Canadian Institutes of Health Research.

Objective: Receptor-interacting protein kinase 1 (RIPK1) orchestrates the decision between cell survival and cell death in response to tumor necrosis factor (TNF) and other cytokines. Whereas the scaffolding function of RIPK1 is crucial to prevent TNF-induced apoptosis and necroptosis, its kinase activity is required for necroptosis and partially for apoptosis. Although TNF is a proinflammatory cytokine associated with β-cell loss in diabetes, the mechanism by which TNF induces β-cell demise remains unclear. Methods: Here, we dissected the contribution of RIPK1 scaffold versus kinase functions to β-cell death regulation using mice lacking RIPK1 specifically in β-cells (Ripk1β-KO mice) or expressing a kinase-dead version of RIPK1 (Ripk1D138N mice), respectively. These mice were challenged with streptozotocin, a model of autoimmune diabetes. Moreover, Ripk1β-KO mice were further challenged with a high-fat diet to induce hyperglycemia. For mechanistic studies, pancreatic islets were subjected to various killing and sensitising agents. Results: Inhibition of RIPK1 kinase activity (Ripk1D138N mice) did not affect the onset and progression of hyperglycemia in a type 1 diabetes model. Moreover, the absence of RIPK1 expression in β-cells did not affect normoglycemia under basal conditions or hyperglycemia under diabetic challenges. Ex vivo, primary pancreatic islets are not sensitised to TNF-induced apoptosis and necroptosis in the absence of RIPK1. Intriguingly, we found that pancreatic islets display high levels of the antiapoptotic cellular FLICE-inhibitory protein (cFLIP) and low levels of apoptosis (Caspase-8) and necroptosis (RIPK3) components. Cycloheximide treatment, which led to a reduction in cFLIP levels, rendered primary islets sensitive to TNF-induced cell death which was fully blocked by caspase inhibition. Conclusions: Unlike in many other cell types (e.g., epithelial, and immune), RIPK1 is not required for cell death regulation in β-cells under physiological conditions or diabetic challenges. Moreover, in vivo and in vitro evidence suggest that pancreatic β-cells do not undergo necroptosis but mainly caspase-dependent death in response to TNF. Last, our results show that β-cells have a distinct mode of regulation of TNF-cytotoxicity that is independent of RIPK1 and that may be highly dependent on cFLIP.

Summary: Background: The most near-term clinical application of genome-wide association studies in lung cancer is a polygenic risk score (PRS). Methods: A case-control dataset was generated consisting of 4002 lung cancer cases from the LORD project and 20,010 ethnically matched controls from CARTaGENE. A genome-wide PRS including >1.1 million genetic variants was derived and validated in UK Biobank (n = 5419 lung cancer cases). The predictive ability and diagnostic discrimination performance of the PRS was tested in LORD/CARTaGENE and benchmarked against previous PRSs from the literature. Stratified analyses were performed by smoking status and genetic risk groups defined as low (80th percentile) PRS. Findings: The phenotypic variance explained and the effect size of the genome-wide PRS numerically outperformed previous PRSs. Individuals with high genetic risk had a 2-fold odds of lung cancer compared to low genetic risk. The PRS was an independent predictor of lung cancer beyond conventional clinical risk factors, but its diagnostic discrimination performance was incremental in an integrated risk model. Smoking increased the odds of lung cancer by 7.7-fold in low genetic risk and by 11.3-fold in high genetic risk. Smoking with high genetic risk was associated with a 17-fold increase in the odds of lung cancer compared to individuals who never smoked and with low genetic risk. Interpretation: Individuals at low genetic risk are not protected against the smoking-related risk of lung cancer. The joint multiplicative effect of PRS and smoking increases the odds of lung cancer by nearly 20-fold. Funding: This work was supported by the CQDM and the IUCPQ Foundation owing to a generous donation from Mr. Normand Lord.

Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

This study demonstrates the application of a new experimental technique for laboratory-scale simulation of the open-die forging process, known as cogging, an intermediate hot-working process necessary to design an optimised microstructure in the advanced engineering titanium alloy Ti-6Al-4V. Small test-bars of Ti-6Al-4V alloy were subjected to multi-directional cogging operations at elevated temperatures (950–1050 °C). The as-received material, prior to forging, underwent heat treatments to coarsen the initial grain structure, to better simulate the industrial-scale intermediate microstructure (i.e., β recrystallised) and to help prove the capability of the set-up to achieve microstructure modification via globularisation (below β-transus), and recrystallisation (dynamic and static) and recovery mechanisms (above β-transus) within the cogged material. The influences of hot working parameters on deformation localisation, width of α platelets, and globularisation within the resulting microstructure variation have been investigated using light microscopy (LM), Vickers hardness (HV) testing, and electron backscatter diffraction (EBSD). The cogged Ti-6Al-4V alloy specimens underwent various microstructural evolution stages after hot forging, thus indicating successful application of the designed miniaturised open-die forging apparatus for high temperature experimentation and characterisation studies. This will be suitable for low-cost small-scale trials to determine the key process parameters affecting the onset of microstructure evolution during open-die forging (e.g., ingot-to-billet conversion) of the Ti-6Al-4V alloy, prior to large-scale trials which are rather more expensive.

Background: Transcranial ultrasound stimulation (TUS) is a non-invasive brain stimulation technique; when skull aberrations are compensated for, this technique allows, with millimetric accuracy, circumvention of the invasive surgical procedure associated with deep brain stimulation (DBS) and the limited spatial specificity of transcranial magnetic stimulation. Objective: /hypothesis: We hypothesize that MR-guided low-power TUS can induce a sustained decrease of tremor power in patients suffering from medically refractive essential tremor. Methods: The dominant hand only was targeted, and two anatomical sites were sonicated in this exploratory study: the ventral intermediate nucleus of the thalamus (VIM) and the dentato-rubro-thalamic tract (DRT). Patients (N = 9) were equipped with MR-compatible accelerometers attached to their hands to monitor their tremor in real-time during TUS. Results: VIM neurostimulations followed by a low-duty cycle (5 %) DRT stimulation induced a substantial decrease in the tremor power in four patients, with a minimum of 89.9 % reduction when compared with the baseline power a few minutes after the DRT stimulation. The only patient stimulated in the VIM only and with a low duty cycle (5 %) also experienced a sustained reduction of the tremor (up to 93.4 %). Four patients (N = 4) did not respond. The temperature at target was 37.2 ± 1.4 °C compared to 36.8 ± 1.4 °C for a 3 cm away control point. Conclusions: MR-guided low power TUS can induce a substantial and sustained decrease of tremor power. Follow-up studies need to be conducted to reproduce the effect and better to understand the variability of the response amongst patients. MR thermometry during neurostimulations showed no significant thermal rise, supporting a mechanical effect.

Open biomes such as grasslands, savannas, shrublands are associated with many global biodiversity hotspots, and cover ∼60% of land globally. Yet, extensive and increasing anthropogenic activities threaten their functioning and biodiversity. Here, we argue that, in open biomes, researchers and stakeholders (e.g., policy-makers, practitioners) should more comprehensively acknowledge that more than half of a plant’s biomass is typically located belowground. Not only fine roots but different belowground coarse organs of plants (e.g., thick roots, rhizomes) play key ecosystem functions that have been largely neglected in basic and applied ecology. By more accurately accounting for the distribution of these organs along ecological gradients, their biomass turnover and decomposition rate, we would improve estimates of carbon cycling (core in climate change mitigation policies) as well as ameliorating conservation efforts focused on open biomes worldwide.

Background: There is no definitive evidence of the prognosis impact of histological variants (HVs) in patients who undergo surgical resection of a nonmetastatic renal cell carcinoma (nm-RCC) with venous tumor thrombus (TT). Objective: To investigate the impact of HVs on the prognosis of patients with nm-RCC with TT after radical surgery. Design, setting, and participants: Patients who underwent radical nephrectomy with the removal of the venous TT for an nm-RCC were included in a retrospective study. Outcome measurements and statistical analysis: Three groups were identified: clear cell (ccRCC), papillary (pRCC), and chromophobe (chRCC) RCC. The primary outcome measures (disease-free and overall survival [OS]) were assessed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional hazard models were used to study the impact of HVs on survival. Results and limitations: A total of 873 patients were included. The histological subtypes were distributed as follows: ccRCC in 780 cases, pRCC in 58 cases, and chRCC in 35 cases. At the time of data analysis, 612 patients were recurrence free and 228 had died. A survival analysis revealed significant differences in both OS and recurrence-free survival across histological subtypes, with the poorest outcomes observed in pRCC patients (p

CDSupdate is a Python package that automates the process of retrieving, processing, and managing climate data from the Copernicus Climate Change Service (C3S) Climate Data Store (CDS). The tool generates daily climate data summaries, performs calculations to create custom variables such as relative humidity and heat index which serve as risk assessments, and organizes the data into a user-friendly format. By simplifying data retrieval and performing on-the-fly calculations, it saves users valuable time and effort, enabling more focus on data analysis and interpretation.

Objectives: Sexual transmission of extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) is suspected. We aimed to identify clusters of sexual behavior associated with ESBL-E carriage among individuals at risk of sexually transmitted infections (STI). Methods: In this cross-sectional study, patients attending an STI-screening center and human immunodeficiency virus outpatient clinic in Paris, France between 2018 and 2019 were asked questions on the following sexual activities in the last 6 months: receptive/insertive anal intercourse, passive/active rimming, receptive/insertive fellatio, receptive/insertive fisting, receptive/insertive fingering, active/passive cunnilingus. ESBL-E carriage was determined from rectal swabs. Bayesian latent class analysis was used to identify clusters of sexual activity, which were then associated with ESBL-E carriage using logistic regression. Results: Among 1211 men who have sex with men (MSM), those belonging to two latent classes with higher prevalence of insertive fingering and active rimming (ESBL-E prevalence=15.3%, N = 124 and 16.0%, N = 100) and one class with higher proportions of all behaviors (24.3%, N = 70) had a higher risk of ESBL-E carriage compared to those in a class with few sexual behaviors (7.3%, N = 259) after adjustment. Among 439 other men and 479 women, no clear associations between sexual clusters and ESBL-E carriage were observed. Conclusions: Sexual behaviors are associated with varying degrees of ESBL-E carriage, particularly among MSM.

Background: Structured and supervised physical exercise and cognitive training are two efficient ways to enhance cognition in older adults. Performing both within a combined intervention could maximize their effect on cognition due to their potential synergy on brain functions. During the COVID-19 pandemic, these interventions were particularly relevant due to the collateral impact of social restrictions regarding physical activity and the level of cognitive stimulation. However, the benefits of remotely monitored intervention combining physical exercise and cognitive training for older adult cognition remain to be demonstrated. Methods: 127 older adults (age: 65.20 ± 7.95) were randomized in two arms, encouraging self-engagement in six months of home-based physical exercise alone or combined with cognitive training, monitored by phone once a week. Neuropsychological assessment was performed under videoconference supervision at baseline and after three and six months. Composite Z-scores were calculated for processing speed, executive functioning, working, and episodic memory to assess changes after three and six months of training. The weekly metabolic expenditure of self-reported activities was estimated using the compendium of physical activity to distinguish participants performing higher and lower doses of exercise (median split). Results: 106 participants (83.46 %) completed the 6-month training. Results showed a greater Z-score change in executive functioning for participants in the combined arm than those who only exercised (F = 4.127, p = 0.046, ηp2 = 0.050). Group x Exercise dose interaction was observed for episodic memory Z-score change (F = 6.736, p = 0.011, ηp2 = 0.070), with a greater improvement for participants performing higher doses of exercise compared to those who performed a lower dose, only in exercise alone arm. Performing a higher dose of exercise increased the working memory Z-score change in both intervention arms compared to a lower dose (F = 7.391, p = 0.008, η p2 = 0.076). Conclusion: Remote combined training may lead to larger improvement in executive functioning than exercise alone. Physical exercise showed a dose-related improvement in working and episodic memory performances. The combination of cognitive interventions mitigated the effects of exercise on episodic memory. These results suggest that home-based exercise and cognitive training may help improve older adults' cognition. Trial registration: COVEPIC was retrospectively registered on December 03, 2020. Clinical trials Identifier: NCT04635462 - https://clinicaltrials.gov/ct2/show/record/NCT04635462?term=NCT04635462&draw=2&rank=1

Objectives: Chlamydia Trachomatis (CT) is the most sexually transmitted infection in France. This study aimed to assess the feasibility of systematic screening for CT among people attending a preventive health examination in Health Examination Centres (HECs) and to compare positive CT cases according to deprivation. Design: A cross-sectional multicentre study in thirteen HECs in France in January 2018. Methods: Self-sampling CT screening was proposed among 18–25 years women and 18–30 years men, who were sexually active and without recent CT treatment. Related data and referred specimens were collected among attendees for the study, including deprivation and health status. CT positivity was estimated by genders. We explored association between CT infection and deprivation by univariate and multivariate modelling. Results: The CT screening was proposed to 1701 eligible young people. 90.1 % [88.6–91.5] accepted and participated with 43.6 % being women, 54.3 % being deprived people. 75.4 % [72.1–78.6] screened women performed self-taken vaginal swabs and others took urinary tests. Screening was conducted in 1486 people. Overall prevalence of CT infection was 4.7 % [3.7%–5.9 %], significantly higher for women than men (6.4 % vs 3.4 %, p=0.009). Among women, being deprived increased the likelihood of CT positivity (aOR 4.95; 95 % CI 2.02 to 12.00) more than it did for men. Conclusions: Individual deprivation was significantly associated with having a CT infection among women. The feasibility of CT screening in HECs was demonstrated, with a high acceptance, and led to the implementation of CT screening in all HECs. Promoting access to CT screening to deprived population might contribute to reduce social inequalities in health.

Background: Controlled substances (CS) are ‘diverted’ (stolen) from healthcare facilities via many integrated and diverse mechanisms due to a lack of safeguards. There remains a gap in understanding how healthcare workers (HCWs) leverage their social networks (e.g., their role/tasks and interactions with other roles/tasks) within the medication use process (MUP) that contribute to diversion. Social network analysis (SNA) is an analytic approach used to map and analyze social connections, which can help identify influential interdependence between HCWs and tasks susceptible to drug diversion. Objectives: To map the social network structures of MUP tasks vulnerable to CS diversion in two Inpatient pharmacies and compare diversion risks by identifying influential tasks and HCWs. Methods: This was an exploratory sequential mixed methods study conducted in the Inpatient pharmacies at two large hospitals in Toronto, Canada. Initial analysis used previously collected clinical observation data to identify key pharmacy roles and tasks vulnerable to CS diversion. Subsequently, a cross-sectional survey was conducted to collect demographic information on HCWs and assess their engagement in the identified vulnerable tasks. Clinical observations and survey data were used to perform two-mode SNA to identify connections between HCWs and tasks susceptible to drug diversion. Results: The analysis identified different network structures across both sites but highlighted the importance of strategic Pharmacist or Technician Supervisor oversight to moderate-high vulnerability tasks. Pharmacy technicians were found to be the network's most central actors, while Pharmacists had a more supportive role on the network's periphery, providing oversight. Across both sites, there was strong connectivity between HCWs and tasks, indicating a higher level of security against potential undetected diversion. Conclusion: By strategically involving Pharmacists or Technician Supervisors, diversion risk can be mitigated through cross-checking and quality control. Through identifying the network structure of each unit, hospitals can identify opportunities for future interventions to prevent diversion.

Mo2Ti2C3Tx MXene materials, bare or loaded with strongly anchored single Pt atoms, were investigated using various methods, including STEM, XPS, XAS and DFT calculations. Upon Pt impregnation, the delaminated Mo-rich MXene surface undergoes partial oxidation, which is reversed by an H2 thermal treatment at 400 °C. The optimized MXene shows high catalytic activity for CO2 hydrogenation to CO and smaller amounts of methane and methanol. Around and above the pretreatment temperature of 400 °C, the MXene is gradually defunctionalized from O- and F-containing groups and depleted in carbidic carbon, leading to deactivation. Single Pt atoms are cationic after impregnation, and reduce upon H2 treatment, filling surface Mo vacancies. Pt addition increases the MXene activity, in particular by facilitating H2 dissociation, but has little effect on the single-atom catalyst selectivity and on the rate dependence upon reactant partial pressures. The lowest Pt loading leads to the highest turnover frequency, indicating that the MXene surface sites are key to CO2 activation.

Summary: Background: In industrialized countries, the incidence of inflammatory bowel disease (IBD) appears stabilized. This study examined the incidence and phenotype of IBD in Northern France over a 30-year period. Methods: Including all IBD patients recorded in the EPIMAD population-based registry from 1988 to 2017 in Northern France, we described the incidence and clinical presentation of IBD according to age, sex and time. Findings: A total of 22,879 incident IBD cases were documented (59% (n = 13,445) of Crohn’s disease (CD), 38% (n = 8803) of ulcerative colitis (UC), 3% (n = 631) of IBD unclassified (IBDU)). Over the study period, incidence of IBD, CD and UC was 12.7, 7.2 and 5.1 per 105 person-years, respectively. The incidence of CD increased from 5.1/105 in 1988–1990 to 7.9/105 in 2015–2017 (annual percent change (APC): +1.9%, p

In this study, we utilised computational fluid dynamics to investigate the behaviour of open-channel basaltic lava flows navigating bends on shield volcanoes. Our focus was on understanding the relationship between flow velocity, rheology, and bend geometry. Employing a simple Force Balance Model (FBM), which considers the equilibrium between hydrostatic pressure and centrifugal force, we accurately approximated the changes in the height of the lava’s free surface through various bend geometries. Our analysis includes examining the influence of channel depth, width, and bend radius on the flow, revealing that variations in these parameters significantly affect the flow’s vertical displacement. Additionally, the bend sector angle emerged as a critical factor, indicating a minimum angle necessary for the flow to fully develop before exiting the bend.Further, we assessed the applicability of the Shallow Water Equations (SWE) for modelling the inertial displacement of the lava flow in bends, finding a good fit. The study extended to comparing the FBM’s predictions of the tilt angle of the flow’s free surface with the SWE results, showing notable agreement under specific conditions, particularly at a bend angle of 90 degrees. The impact of fluid density was also considered, revealing that density is a contributing factor to the development of the wetted line in the bend, a factor that is not captured by the simple FBM model. Finally, we explored different rheologies akin to natural lava flows, such as viscoplastic flow, and determined that factors like yield stress, consistency index, and power law index have a small impact on the flow behaviour in a steady-state condition within a bend.

This study aims to assess the level of sustainability in vegetable-based agrifood production systems in Benin and to propose actions to enhance sustainability, food safety, and year-round production in the vegetable production systems. Semi-structured interviews were conducted with 200 vegetable farmers in contrasting agroecological areas (with areas of extensive production of staples and intensive production of vegetables), using the “Indicateur de Durabilité des Exploitations Agricoles” (IDEA) framework (an on-farm sustainability index). Most of the surveyed vegetable farmers produced a wide range of crops, including leafy vegetables (amaranth, African eggplant, and African basil) and peppers, grown by more than 50% of the farmers. The average scores achieved by the vegetable farms regarding three dimensions of sustainability—ecological, social, and economic—were 35, 41, and 63, respectively, out of a maximum score of 100. All three sustainability dimensions of the vegetable farms were, on average, at a low level and improvements were needed for them to reach an acceptable standard. The vegetable farms located in the south of Benin had, on average, a higher sustainability score than those in the north: around 50% of vegetable farms in the south had a medium score, while the sustainability level of almost 75% of vegetable farms in the north was low. Interventions seeking to improve the sustainability of vegetable farms in Benin should focus on the promotion and adoption of eco-responsible practices that improve on-farm biodiversity, water conservation, and the effective allocation and management of land and labor, to mitigate the environmental impacts of vegetable production.

Summary: Here, we present a lysate-based split-luciferase assay for examining protein-protein interactions (PPIs) in HEK293T cell lysates, exemplified by interactions between subunits of protein phosphatase PP1. We describe steps for storing and re-using lysates, sensor design, assay setup/optimization, and high-throughput screening of compound libraries. We then detail procedures for applying the assay as a research tool to characterize the dynamics of PPIs, which we illustrate with specific examples.For complete details on the use and execution of this protocol, please refer to Claes and Bollen.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Purpose: To describe the clinical presentation and management of severe capecitabine-induced corneal toxicity. Observations: A 71-year-old woman presented with severe bilateral vision loss. Four months earlier, capecitabine was initiated for a metastatic invasive ductal carcinoma. Biomicroscopy revealed bilateral whorl-like corneal epitheliopathy accompanied by metaplasia, keratinization and subepithelial fibrosis. After consulting the treating oncologist, capecitabine treatment was discontinued. Initially, a non-surgical approach was adopted and intensive topical dexamethasone treatment was applied. Despite capecitabine discontinuation and topical steroid treatment, visual acuity progressively declined. Bilateral corneal scraping and bandage contact lens fitting was performed. This resulted in significant improvement of visual acuity, corneal surface regularity and quality of life. Conclusion and importance: We report the first case of severe visual impairment due to capecitabine-induced corneal toxicity. Early corneal scraping, especially when confronted with profound vision loss, may yield better outcomes compared to relying on spontaneous recovery after capecitabine discontinuation. Patients experiencing ocular discomfort and vision loss, while receiving capecitabine therapy, should be referred for semi-urgent ophthalmological examination.

Savannas cover more than 20% of the Earth and account for the third largest stock of global aboveground biomass yet estimates of their above ground biomass density (AGBD) are very inaccurate. The Global Ecosystem Dynamic Investigation (GEDI) sensor provides near-global full-waveform LiDAR data with 25 m footprints, from which various structural metrics are derived that are used to predict footprint level AGBD. The current GEDI L4A AGBD product uses a comprehensive Forest Structure and Biomass Database (FSBD) to develop models for specific plant functional types and geographic regions, but southern African savannas have been underrepresented in the reference data. The objectives of this study were to (i) validate GEDI L4A AGBD in South African savannas using field measurements and ALS datasets and (ii) develop and evaluate local GEDI footprint-level AGBD estimates from multiple L2A and L2B metrics. The local GEDI AGBD models outperformed GEDI L4A AGBD (R2 = 0.42, RMSE = 12 Mg/ha, %RMSE = 79.5%) with higher R2 and smaller error measures. The local GEDI AGBD using a random forest model (RF) had the highest R2 of 0.71 and lowest %RMSE of 53.3%, while the generalized linear model (GLM) results provided the lowest Relative Mean Systematic Deviation (RMSD) of 9.2%, which was half that of RF model. L4A significantly underestimated AGBD with an RMSD up to −37%. This highlights the importance and benefits of local calibration of biomass models to unlock the full potential of GEDI metrics for estimating AGBD. The field and ALS data have subsequently been contributed to the GEDI FSBD and should be used in calibration of future versions of GEDI L4A AGBD product. This research paves the way for the integration of the local GEDI AGBD estimates with other sensors, notable the eminent NISAR mission, to derive regional to global gridded AGBD products that will enable the monitoring of savanna carbon stocks.

The paper evaluates the EW-1000 Atmospheric Water Generation-Vapor Compression Refrigeration system (AWG-VCRS) as a sustainable alternative to seawater desalination in the GCC. Conducted in Masdar City, Abu Dhabi, from July 2023 to January 2024, the study measured temperature, humidity, energy consumption, and water production. Key findings include a peak water production of 1500 LPD in September and an average Specific Energy Consumption (SEC) of 0.26 kWh/L. Productivity decreased by 71 % in cooler, dryer months. With a coefficient of performance (COP) of 3.6, the system aligns with conventional air conditioners, highlighting its potential for enhancing water security in arid regions.

Studying insect fossils, particularly those preserved as compressions in sedimentary matrices, can be difficult due to the taphonomic processes that often result to poor preservation and contrast of structures compared to the embedding matrix. To address this, we propose a user-friendly and simple methodology based on UV-light to study insect fossils and select specimens of interest for more advanced imagery exploration. While UV-light imaging has been previously applied to compressions of arthropod fossils, it typically involved laser light sources. Our approach allows the investigation of fossils using an affordable, compact, and portable UV-light source, along with a simple and replicable low-cost protocol. • The methodology is based on UV-light induced natural fluorescence of sediment and fossil remains. • UV-light is effective on compression fossils to gain natural contrast and enhance observation of body structures like veins or setae on wings. • UV-light is effective to reveal palaeoecological information such as pollen grains preserved on specimens, especially near or on putative pollinator or pollen-eating taxa.

In recent years the use of Design Science Research (DSR), a research methodology that has proved fruitful in various domains, has expanded. This contribution shows how the fundamentals of DSR translate into the field of applied psychology and how they might offer formal grounding to novel psychological approaches. The validatory value of DSR is illustrated by applying its methodology to the case of solution-focused psychology. This leads to an articulation of the solution-focused approach that allows to be tested along the lines set out by DSR. Finally, recommendations are given for the use of DSR in applied psychology.

Mechanical harvesting of wild blueberries on uneven topography is challenging for the operators, emphasizing the need for harvester header automation. This research aims to develop accurate Digital Elevation Models (DEMs) and map plant height using a DJI Matrice-300 RTK Drone equipped with two distinct DJI sensors, Zenmuse P1 and Zenmuse L1. Accuracy assessment involved comparing drone-generated DEMs with elevation data from a Global Navigation Satellite System receiver, Emlid RS2. Results indicate that the P1 camera outperformed the L1 sensor in estimating DEMs within wild blueberry fields, with root mean square error values ranging from 0.36 to 1.04 cm and 1.29 to 1.70 cm for the P1 and L1 sensors, respectively. Furthermore, P1 demonstrated a significantly lower standard deviation than L1 in selected fields. The P1 imagery dataset determined wild blueberry plant heights with standard deviations of 3.66 cm and 4.77 cm for Field-A and Field-B, respectively. The precise DEMs and plant height information can be integrated into the control system of the wild blueberry harvester, facilitating automation that accounts for spatial variations in plant height, slope, and fruit zone within fields. Implementing an automated harvester holds promise for reducing fruit losses, enhancing grower profitability, and alleviating operator stress.

A robust and cost-effective pilot solar-powered membrane bioreactor (MBR) with downstream granular activated carbon (GAC) filter hospital wastewater treatment was developed for the Lubaga hospital in Kampala, Uganda. The MBR-GAC pilot included a 25 m2 ultrafiltration (UF) module, a 100 kg GAC filter, 20 photovoltaic panels totaling 7 kWp and a 3.55 kWh supercapacitor energy storage unit to produce non-potable and reusable water for toilet flushing, cleaning and irrigation. The pilot operated with 43% clean energy autonomy with grid and diesel generator backup for power outages of more than 1 hour. The MBR pilot produced an average flux of 10–15 L m–2 h–1 with 50% total organic carbon (TOC) removal. The nitrification, denitrification and filtration tanks were separated to achieve a nitrification of 80% and denitrification of 20%. The removal of typical hospital pharmaceutical residues that could not be reduced by the MBR increased to approximately 90% after the downstream GAC filter was upgraded. The removal efficiency of the GAC decreased to approximately 25% at 4,290 bed volume (BV). The significant increase of 75% in the removal efficiency of diclofenac in the MBR was attributed to the acclimation of the activated sludge. The quality of the treated wastewater from the pilot plant was sufficient for reuse by irrigation of the hospital garden, toilet flushing and cleaning. Finally, the study discussed ways to optimize the design and operation of the plant. The pilot is scalable to be replicated elsewhere and adapted in an efficient and cost-effective manner in sub-Saharan countries in Africa.

Summary: Gender equality has been a crosscutting issue in Horizon 2020 with three objectives: gender balance in decision-making, gender balance and equal opportunities in project teams at all levels, and inclusion of the gender dimension in research and innovation content. Between 2017 and 2022, the EU funded, in collaboration with national agencies, 13 transnational projects under “GENDER-NET Plus” that explored how to best integrate both sex and gender into studies ranging from social sciences, humanities, and health research. As the projects neared completion, forty researchers from these interdisciplinary teams met in November 2022 to share experiences, discuss challenges, and consider the best ways forward to incorporate sex and gender in research. Here, we summarize the reflections from this workshop and provide some recommendations for i) how to plan the studies (e.g., how to define sex and/or gender and their dimensions, rationale for the hypotheses, identification of data that can best answer the research question), ii) how to conduct them (e.g., adjust definitions and dimensions, perform pilot studies to ensure proper use of terminology and revise until consensus is achieved), and iii) how to analyze and report the findings being mindful of any real-world impact.

Summary: Background: Variants in GABRB2, encoding the β2 subunit of the γ-aminobutyric acid type A (GABAA) receptor, can result in a diverse range of conditions, ranging from febrile seizures to severe developmental and epileptic encephalopathies. However, the mechanisms underlying the risk of developing milder vs more severe forms of disorder remain unclear. In this study, we conducted a comprehensive genotype–phenotype correlation analysis in a cohort of individuals with GABRB2 variants. Methods: Genetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function. Findings: Electrophysiological assessments of α1β2γ2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants. Interpretation: The data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic flowchart that aids in predicting the pathogenicity of recently identified variants by considering clinical phenotypes. Funding: This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.

The provided dataset describes the transcriptomic profile of human liver spheroid co-cultures consisting of a human hepatoma cell line (C3A/HepG2 cells) and an immortalized activated human hepatic stellate cell line (LX-2 cells) upon exposure to total parenteral nutrition. High-throughput RNA sequencing was performed using DNBSEQTM sequencing technology. Following the quality check and filtering of raw sequence reads, the clean reads were aligned to the reference human genome and used to determine differential gene expression. Raw and processed data are deposited in the Gene Expression Omnibus with accession number GSE264357. These data could serve further mechanistic studies on parenteral nutrition-induced liver injury and support translational research on intestinal failure-associated liver disease occurring in individuals receiving total parenteral nutrition.

Background and purpose: Dose escalation in external radiotherapy of prostate cancer shows promising results in terms of biochemical disease-free survival. Boost volume delineation guidelines are sparse which may cause high interobserver variability. The aim of this research was to characterize gross tumor volume (GTV) delineations based on multiparametric magnetic resonance imaging (mpMRI) and prostate specific membrane antigen-positron emission tomography (PSMA-PET) in relation to histopathology-validated Gleason grade 4 and 5 regions. Material and methods: The study participants were examined with [68Ga]PSMA-PET/mpMRI prior to radical prostatectomy. Four radiation oncologists delineated GTVs in 15 study participants, on four different image types; T2-weighted (T2w), diffusion weighted imaging (DWI), dynamic contrast enhanced (DCE) and PSMA-PET scans separately. The simultaneous truth and performance level estimation (STAPLE) algorithm was used to generate combined GTVs. GTVs were subsequently compared to histopathology. We analysed how Dice similarity coefficient (DSC) and lesion coverage are affected by using single versus multiple image types as well as by adding a clinical target volume (CTV) margin. Results: Median DSC (STAPLE) for different GTVs varied between 0.33 and 0.52. GTVPSMA-PET/mpMRI generated the highest median lesion coverage at 0.66. Combining different image types achieved similar lesion coverage as adding a CTV margin to contours from a single image type, while reducing non-malignant tissue inclusion within the target volume. Conclusion: The combined use of mpMRI or PSMA-PET/mpMRI shows promise, achieving higher DSC and lesion coverage while minimizing non-malignant tissue inclusion, in comparison to the use of a single image type with an added CTV margin.

Summary: Human CD8 tumor-infiltrating lymphocytes (TILs) with impaired effector functions and PD-1 expression are categorized as exhausted. However, the exhaustion-like features reported in TILs might stem from their activation rather than the consequence of T cell exhaustion itself. Using CRISPR-Cas9 and lentiviral overexpression in CD8 T cells from non-cancerous donors, we show that the T cell receptor (TCR)-induced transcription factor interferon regulatory factor 4 (IRF4) promotes cell proliferation and PD-1 expression and hampers effector functions and expression of nuclear factor κB (NF-κB)-regulated genes. While CD8 TILs with impaired interferon γ (IFNγ) production exhibit activation markers IRF4 and CD137 and exhaustion markers thymocyte selection associated high mobility group box (TOX) and PD-1, activated T cells in patients with COVID-19 do not demonstrate elevated levels of TOX and PD-1. These results confirm that IRF4+ TILs are exhausted rather than solely activated. Our study indicates, however, that PD-1 expression, low IFNγ production, and active cycling in TILs are all influenced by IRF4 upregulation after T cell activation.

Summary: Background: Research in healthy young adults shows that characteristic patterns of brain activity define individual “brain-fingerprints” that are unique to each person. However, variability in these brain-fingerprints increases in individuals with neurological conditions, challenging the clinical relevance and potential impact of the approach. Our study shows that brain-fingerprints derived from neurophysiological brain activity are associated with pathophysiological and clinical traits of individual patients with Parkinson’s disease (PD). Methods: We created brain-fingerprints from task-free brain activity recorded through magnetoencephalography in 79 PD patients and compared them with those from two independent samples of age-matched healthy controls (N = 424 total). We decomposed brain activity into arrhythmic and rhythmic components, defining distinct brain-fingerprints for each type from recording durations of up to 4 min and as short as 30 s. Findings: The arrhythmic spectral components of cortical activity in patients with Parkinson’s disease are more variable over short periods, challenging the definition of a reliable brain-fingerprint. However, by isolating the rhythmic components of cortical activity, we derived brain-fingerprints that distinguished between patients and healthy controls with about 90% accuracy. The most prominent cortical features of the resulting Parkinson’s brain-fingerprint are mapped to polyrhythmic activity in unimodal sensorimotor regions. Leveraging these features, we also demonstrate that Parkinson’s symptom laterality can be decoded directly from cortical neurophysiological activity. Furthermore, our study reveals that the cortical topography of the Parkinson’s brain-fingerprint aligns with that of neurotransmitter systems affected by the disease’s pathophysiology. Interpretation: The increased moment-to-moment variability of arrhythmic brain-fingerprints challenges patient differentiation and explains previously published results. We outline patient-specific rhythmic brain signaling features that provide insights into both the neurophysiological signature and symptom laterality of Parkinson’s disease. Thus, the proposed definition of a rhythmic brain-fingerprint of Parkinson’s disease may contribute to novel, refined approaches to patient stratification. Symmetrically, we discuss how rhythmic brain-fingerprints may contribute to the improved identification and testing of therapeutic neurostimulation targets. Funding: Data collection and sharing for this project was provided by the Quebec Parkinson Network (QPN), the Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer’s Disease (PREVENT-AD; release 6.0) program, the Cambridge Centre for Aging Neuroscience (Cam-CAN), and the Open MEG Archives (OMEGA). The QPN is funded by a grant from Fonds de Recherche du Québec - Santé (FRQS). PREVENT-AD was launched in 2011 as a $13.5 million, 7-year public-private partnership using funds provided by McGill University, the FRQS, an unrestricted research grant from Pfizer Canada, the Levesque Foundation, the Douglas Hospital Research Centre and Foundation, the Government of Canada, and the Canada Fund for Innovation. The Brainstorm project is supported by funding to SB from the NIH (R01-EB026299-05). Further funding to SB for this study included a Discovery grant from the Natural Sciences and Engineering Research Council of Canada of Canada (436355-13), and the CIHR Canada research Chair in Neural Dynamics of Brain Systems (CRC-2017-00311).

Background: The metastasis of tumors into bone tissue typically leads to intractable pain that is both very disabling and particularly difficult to manage. We investigated here whether riluzole could have beneficial effects for the treatment of prostate cancer-induced bone pain and how it could influence the development of bone metastasis. Methods: We used a bone pain model induced by intratibial injection of human PC3 prostate cancer cells into male SCID mice treated or not with riluzole administered in drinking water. We also used riluzole in vitro to assess its possible effect on PC3 cell viability and functionality, using patch-clamp. Results: Riluzole had a significant preventive effect on both evoked and spontaneous pain involving the TREK-1 potassium channel. Riluzole did not interfere with PC3-induced bone loss or bone remodeling in vivo. It also significantly decreased PC3 cell viability in vitro. The antiproliferative effect of riluzole is correlated with a TREK-1-dependent membrane hyperpolarization in these cells. Conclusion: The present data suggest that riluzole could be very useful to manage evoked and spontaneous hypersensitivity in cancer-induced bone pain and has no significant adverse effect on cancer progression.