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Abstract Background The use of mobile health apps for remote monitoring has considerable potential for patient care. However, more research is needed to gather patients’ experience with their use. This study evaluates heart failure patients’ experience of the effects of remote monitoring on the management of heart failure (HF) using a smartphone app, the challenges faced in such use, and patients’ suggestions for improving the efficacy of this device. Method A qualitative study was conducted with all patients who had used the TakeCare™ app for at least three months during the exploratory phase of the Continuum project. Patients were recruited before COVID-19 began, and they used the app during this period. The app allows patients to submit their daily vital signs and answer questions about their symptoms to help the clinical professionals adjust their treatment plan as needed. Individual interviews were conducted by telephone or videoconference using a semi-structured individual interview guide. All interviews were recorded, transcribed and analyzed using the thematic analysis method. Results Of the 29 patients invited, 5 had since died, 10 did not respond, two gave positive feedback on the app but declined the interview, and 12 patients agreed to participate in an individual interview. The participants all liked the app’s ease of use. They particularly praised the contribution it made to monitoring their disease, both by themselves and by clinicians. The app also allowed them to stay connected to their clinical team and have better access to healthcare professionals. Patients suggested, as an improvement, that the feedback and communication features should be personalized to make them more individualized and interactive. Conclusion The TakeCare™ smartphone app was well received by patients with heart failure. Its use could facilitate better remote monitoring of heart conditions in the home as well as improve access to clinical teams.

Abstract Background Cocaine craving is a central symptom of cocaine use disorders (CUD). Virtual reality cue-exposure therapy for craving (VRCET) allows more immersive, realistic, and controllable exposure than traditional non-VR cue-exposure therapy (CET), whose efficacy is limited in treating substance use disorders. The purpose of this study is to evaluate the efficacy and acceptability of VRCET, as a stand-alone and add-on intervention (i.e., combined with cognitive therapy), compared to a picture-based CET (PCET), in reducing self-reported cocaine craving in inpatients hospitalized for CUD. Methods Fifty-four inpatients hospitalized for CUD will be randomized in one of two intensive 3-week treatment arms: 10 meetings/2-week treatment of VRCET plus 5 meetings/1-week treatment of memory-focused cognitive therapy (MFCT; experimental arm), or 15 meetings/3-week treatment of PCET (active control arm). The Craving Experience Questionnaire (CEQ – F & S) will be used to assess the primary outcome, i.e., the post-treatment decrease of self-reported cocaine craving frequency (within the past 2 weeks) and intensity scores (in VR exposure to cocaine cues). Secondary endpoints include urinary, physiological, and self-reported cocaine use-related measures. Assessments are scheduled at pretreatment, after 2 weeks of treatment (i.e., VRCET vs. PCET), post-treatment (3 weeks, i.e., VRCET + MFCT vs. PCET), and at 1-month follow-up. Acceptability will be evaluated via (i) the Spatial Presence for Immersive Environments – Cybersickness along VRCET and (ii) the Client Satisfaction Questionnaires after 2 weeks of treatment and post-treatment. Discussion This study will be the first to evaluate the acceptability and efficacy of VRCET for CUD, as a psychotherapeutic add-on, to reduce both cocaine craving frequency and intensity. Additionally, this study will provide evidence about the specific interest of VRCET, compared to a non-VR-based CET, as a cue reactivity and exposure paradigm for treating substance use disorders. Trial registration NCT05833529 [clinicaltrials.gov]. Prospectively registered on April 17, 2023.

Abstract Background Artificial intelligence (AI) technologies are expected to “revolutionise” healthcare. However, despite their promises, their integration within healthcare organisations and systems remains limited. The objective of this study is to explore and understand the systemic challenges and implications of their integration in a leading Canadian academic hospital. Methods Semi-structured interviews were conducted with 29 stakeholders concerned by the integration of a large set of AI technologies within the organisation (e.g., managers, clinicians, researchers, patients, technology providers). Data were collected and analysed using the Non-Adoption, Abandonment, Scale-up, Spread, Sustainability (NASSS) framework. Results Among enabling factors and conditions, our findings highlight: a supportive organisational culture and leadership leading to a coherent organisational innovation narrative; mutual trust and transparent communication between senior management and frontline teams; the presence of champions, translators, and boundary spanners for AI able to build bridges and trust; and the capacity to attract technical and clinical talents and expertise. Constraints and barriers include: contrasting definitions of the value of AI technologies and ways to measure such value; lack of real-life and context-based evidence; varying patients’ digital and health literacy capacities; misalignments between organisational dynamics, clinical and administrative processes, infrastructures, and AI technologies; lack of funding mechanisms covering the implementation, adaptation, and expertise required; challenges arising from practice change, new expertise development, and professional identities; lack of official professional, reimbursement, and insurance guidelines; lack of pre- and post-market approval legal and governance frameworks; diversity of the business and financing models for AI technologies; and misalignments between investors’ priorities and the needs and expectations of healthcare organisations and systems. Conclusion Thanks to the multidimensional NASSS framework, this study provides original insights and a detailed learning base for analysing AI technologies in healthcare from a thorough socio-technical perspective. Our findings highlight the importance of considering the complexity characterising healthcare organisations and systems in current efforts to introduce AI technologies within clinical routines. This study adds to the existing literature and can inform decision-making towards a judicious, responsible, and sustainable integration of these technologies in healthcare organisations and systems.

BackgroundHeart failure (HF) is the primary cause of hospitalization among Canadian patients aged ≥65 years. Care for HF requires regular clinical follow-ups to prevent readmissions and facilitate medical therapy optimization. Multiple barriers lead to therapeutic medical inertia including limited human resources and regional inequities. Remote patient monitoring (RPM) and digital therapeutics (DTx) solutions have been developed to improve HF management, but their adoption remains limited and underexplored. The Continuum project emerged as a collaborative initiative involving a health care center, a software start-up, and an industrial partner. ObjectiveWe aimed to develop and test the feasibility of the Continuum intervention that seamlessly combined an RPM system with a DTx solution for HF within the same software. MethodsA 3-month pre-post pilot study was conducted from October 2020 to June 2021. Patients with HF who owned a smartphone or tablet (having remote patient monitoring [RPM+]), had (1) access to a self-care app where they could enter their vital signs, weight, and HF symptoms and view educational content; (2) daily monitoring of their data by a nurse; and (3) a DTx module with automated HF medication suggestions based on national guidelines, made available to their treating medical team. Bluetooth devices were offered to facilitate data recording. Nurses on RPM monitoring could call patients and arrange appointments with their medical team. Patients without a mobile device or unable to use the app were followed in another group (without remote patient monitoring [RPM–]). ResultsIn total, 52 patients were enrolled in this study (32 RPM+ and 20 RPM–). Among patients owning a mobile device, only 14% (5/37) could not use the app. In the RPM+ group, 47% (15/32) of the patients used the app for more than 80% (67 days) of the 12-week study period. The use of our digital solution was integrated into the regular nursing workday and only 34 calls had to be made by the nurse during the study period. Only 6% (2/32) of the patients in the RPM+ group experienced at least 1 all-cause hospitalization versus 35% (7/20) of the RPM– ones during the follow-up (6%, 2/32 vs 25%, 5/20 for HF hospitalization) and patients were more likely to have their HF therapy optimized if the DTx solution was available. Quality of life improved in patients compliant with the use of the mobile app (mean score variation +10.6, SD 14.7). ConclusionsThis pilot study demonstrated the feasibility of implementing our digital solution, within the specific context of HF. The seamless integration of Continuum into nursing workflow, mobile app accessibility, and adoption by patients, were the 3 main key learning points of this study. Further investigation is required to assess the potential impacts on hospitalizations, drug optimization, and quality of life. Trial RegistrationClinicalTrials.gov NCT05377190; https://clinicaltrials.gov/study/NCT05377190 (pilot study #21.403)

Abstract The effects of low doses of ionizing radiation on atherosclerosis remain uncertain, particularly as regards the generation of pro- or anti-inflammatory responses, and the time scale at which such effects can occur following irradiation. To explore these phenomena, we exposed atheroprone ApoE(−/−) mice to a single dose of 0, 0.05, 0.5 or 1 Gy of 137Cs (γ) administered at a 10.35 mGy min−1 dose rate and evaluated short-term (1–10 days) and long-term consequences (100 days). Bone marrow-derived macrophages were derived from mice 1 day after exposure. Irradiation was associated with a significant skewing of M0 and M2 polarized macrophages towards the M2 phenotype, as demonstrated by an increased mRNA expression of Retnla, Arg1, and Chil3 in cells from mice exposed to 0.5 or 1 Gy compared with non-irradiated animals. Minimal effects were noted in M1 cells or M1 marker mRNA. Concurrently, we observed a reduced secretion of IL-1β but enhanced IL-10 release from M0 and M2 macrophages. Effects of irradiation on circulating monocytes were most marked at day 10 post-exposure, when the 1 Gy dose was associated with enhanced numbers of both Ly6CHigh and Ly6Low cells. By day 100, levels of circulating monocytes in irradiated and non-irradiated mice were equivalent, but anti-inflammatory Ly6CLow monocytes were significantly increased in the spleen of mice exposed to 0.05 or 1 Gy. Long term exposures did not affect atherosclerotic plaque size or lipid content, as determined by Oil red O staining, whatever the dose applied. Similarly, irradiation did not affect atherosclerotic plaque collagen or smooth muscle cell content. However, we found that lesion CD68+ cell content tended to decrease with rising doses of radioactivity exposure, culminating in a significant reduction of plaque macrophage content at 1 Gy. Taken together, our results show that short- and long-term exposures to low to moderate doses of ionizing radiation drive an anti-inflammatory response, skewing bone marrow-derived macrophages towards an IL-10-secreting M2 phenotype and decreasing plaque macrophage content. These results suggest a low-grade athero-protective effect of low and moderate doses of ionizing radiation.

Abstract Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell receptor signaling and as such is an attractive target for cancer immunotherapy. Although the role of the HPK1 kinase domain (KD) has been extensively characterized, the function of its citron homology domain (CHD) remains elusive. Through a combination of structural, biochemical, and mechanistic studies, we characterize the structure-function of CHD in relationship to KD. Crystallography and hydrogen-deuterium exchange mass spectrometry reveal that CHD adopts a seven-bladed β-propellor fold that binds to KD. Mutagenesis associated with binding and functional studies show a direct correlation between domain-domain interaction and negative regulation of kinase activity. We further demonstrate that the CHD provides stability to HPK1 protein in cells as well as contributes to the docking of its substrate SLP76. Altogether, this study highlights the importance of the CHD in the direct and indirect regulation of HPK1 function.

Streptococcus suis causes diseases in pigs and has emerged as a zoonotic agent. When infected, the host develops an exacerbated inflammation that can lead to septic shock and meningitis. Although neutrophils greatly infiltrate the lesions, their dynamics during S. suis infection remain poorly described. Moreover, very few studies reported on the production and role of a key factor in the regulation of neutrophils: the colony-stimulating granulocyte factor (G-CSF). In this study, we characterized the G-CSF-neutrophil axis in the pathogenesis of S. suis induced disease. Using a mouse model of S. suis infection, we first evaluated the recruitment of neutrophils and their activation profile by flow cytometry. We found that infection provokes a massive neutrophil recruitment from the bone marrow to the blood and spleen. In both compartments, neutrophils displayed multiple activation markers. In parallel, we observed high systemic levels of G-CSF, with a peak of production coinciding with that of neutrophil recruitment. We then neutralized the effects of G-CSF and highlighted its role in the release of neutrophils from the bone marrow to the blood. However, it did not affect bacteremia nor the cytokine storm induced by S. suis. In conclusion, systemic G-CSF induces the release of neutrophils from the bone marrow to the blood, but its role in inflammation or bacterial clearance seems to be compensated by unknown factors. A better understanding of the role of neutrophils and inflammatory mediators could lead to better strategies for controlling the infection caused by S. suis.

Background: Craving is a core symptom of cocaine use disorders (CUD). Inducing craving in exposure to substance cues is of relevant interest for numerous clinical applications. Virtual reality exposure (VRE) might be a promising candidate for improving cue-exposure paradigms but remains almost not studied for cocaine. This feasibility study’s main aim is to assess whether VRE to cocaine cues is capable to induce cocaine craving compared with VRE to neutral cues. Methods: We conducted a within-subjects controlled trial in which cocaine users performed 3 consecutive 10 mins-tasks: VRE to neutral and cocaine cues, and a relaxation-based resting procedure. The primary outcome was the change in Cocaine Craving Questionnaire-Brief (CCQ-Brief) scores between VRE to neutral and cocaine cues. Secondary outcomes included between-tasks changes in scores of cocaine craving, pleasant/unpleasant emotions as well as self-efficacy to cope with craving. Results: We recruited 11 chronic cocaine users including mostly crack smokers (45 %), cocaine snorters (36 %) and injectors (18 %), with 73 % of participants meeting DSM-IV criteria for cocaine dependence and/or abuse. Non-parametrical sign tests indicated significant large increases of CCQ-Brief scores from neutral to cocaine cue-VRE (S(11) = 11, p

Abstract Fully formulated synthetic jet fuel is an aviation turbine fuel that does not contain petroleum‐derived kerosene and comprises the hydrocarbon compound classes n‐alkanes, isoalkanes, cycloalkanes, and aromatics. When the aim is to produce sustainable aviation fuel, one potential process pathway is by indirect liquefaction via Fischer–Tropsch synthesis. Fischer–Tropsch synthesised paraffinic kerosene plus aromatics (FT SPK/A) is a product that is fully formulated and can in principle be qualified as Jet A‐1. The synthetic jet fuel must ultimately meet all of the Jet A‐1 specifications. However, there are still hurdles on the path toward global approval of fully formulated synthetic jet fuel. In this study, several different refining pathways are shown that can be employed to produce FT SPK/A. The refining pathways have the desirable attribute of being generally useful and not limited to a specific refining technology. A case study is also presented in which FT SPK/A was produced, characterised and compared to Jet A‐1 specification requirements. It illustrated that it was practical to produce a fully formulated jet fuel via Fischer–Tropsch refining.

Mucins are large gel-forming polymers inside the mucus barrier that inhibit the yeast-to-hyphal transition of Candida albicans, a key virulence trait of this important human fungal pathogen. However, the molecular motifs in mucins that inhibit filamentation remain unclear despite their potential for therapeutic interventions. Here, we determined that mucins display an abundance of virulence-attenuating molecules in the form of mucin O-glycans. We isolated and cataloged >100 mucin O-glycans from three major mucosal surfaces and established that they suppress filamentation and related phenotypes relevant to infection, including surface adhesion, biofilm formation and cross-kingdom competition between C. albicans and the bacterium Pseudomonas aeruginosa. Using synthetic O-glycans, we identified three structures (core 1, core 1 + fucose and core 2 + galactose) that are sufficient to inhibit filamentation with potency comparable to the complex O-glycan pool. Overall, this work identifies mucin O-glycans as host molecules with untapped therapeutic potential to manage fungal pathogens.

Abstract Companies’ productivity is critical in contemporary warehouse environment to maintain efficiency and competitiveness within their supply chain. Warehousing operations are well known for their impact on the overall supply chain and need to be wisely managed. Among those activities, allocation planning and layout design are some of the most important concepts in practice. Current research tends to emphasize homogeneous environment, which leaves heterogeneous and non-standard cases with less attention, even today. This paper aims to review the literature regarding warehouse allocation planning and layout design methods that could suit practical industry problems, with a focus on heterogeneous and non-standard spare parts. It also aims to describe the current trends in these fields. Following a literature review methodology, a total of fifty-seven articles were reviewed to identify the methods developed and used. The reviewed papers were also investigated in order to identify research gaps and future directions. The analysis concluded that more research is needed to better understand and optimize heterogeneous and non-standard spare parts environments in terms of allocation and layout design. More practical case applications also remain a gap to address. Article highlights This article evaluates 8 concepts/parameters related to warehouse allocation operation. This is to ensure a deep analysis of heterogeneous and non-standard parts presence in literature. A research gap is identified regarding heterogeneous and non-standard parts in warehouse allocation and layout design methods in the scientific literature. This article evaluates 3798 scientific papers over a 20-year timeframe. From this, we present 57 methods and 8 gaps in scientific literature.

Abstract Orthopedic foreign body-associated infection can be difficult to treat due to the formation of biofilms protecting microorganisms from both antimicrobials and the immune system. Exebacase is an antistaphylococcal lysin (cell wall hydrolase) under consideration for local treatment for biofilm-based infections caused by methicillin-resistant Staphylococcus aureus (MRSA). To determine the activity of exebacase, we formed MRSA biofilms on orthopedic Kirschner wires and exposed them to varying concentrations (0.098, 0.98, 9.8 mg/ml) of exebacase and/or daptomycin over 24 h. The biofilm consisted of 5.49 log10 colony forming units (cfu)/K-wire prior to treatment and remained steady throughout the experiment. Exebacase showed significant biofilm reduction at all timepoints (up to 5.78 log10 cfu/K-wire; P 3 log10 cfu/K-wire reduction) observed for up to 12 h for the 0.098 and 0.98 mg/ml concentrations and at 24 h for 9.8 mg/ml. Daptomycin showed significant biofilm reduction, although non-bactericidal, at all time points for 0.98 and 9.8 mg/ml and at 4 and 8 h with 0.098 mg/ml (P

(1) Background: Barrett's esophagus is a major risk factor for esophageal adenocarcinoma. In this pilot study, we employed precision mass spectrometry to map global (phospho)protein perturbations in Barrett's esophagus lesions and adjacent normal tissue to glean insights into disease progression. (2) Methods: Biopsies were collected from two small but independent cohorts. Comparative analyses were performed between Barrett's esophagus samples and adjacent matched (normal) tissues from patients with known pathology, while specimens from healthy patients served as additional controls. (3) Results: We identified and quantified 6810 proteins and 6395 phosphosites in the discovery cohort, revealing hundreds of statistically significant differences in protein abundances and phosphorylation states. We identified a robust proteomic signature that accurately classified the disease status of samples from the independent patient cohorts. Pathway-level analysis of the phosphoproteomic profiles revealed the dysregulation of specific cellular processes, including DNA repair, in Barrett's esophagus relative to paired controls. Comparative analysis with previously published transcriptomic profiles provided independent evidence in support of these preliminary findings. (4) Conclusions: This pilot study establishes the feasibility of using unbiased quantitative phosphoproteomics to identify molecular perturbations associated with disease progression in Barrett's esophagus to define potentially clinically actionable targets warranting further assessment.

Purpose: Laryngeal high-speed videoendoscopy (LHSV) has been recognized as a highly valuable modality for the scientific investigations of vocal fold (VF) vibrations. In contrast to stroboscopic imaging, LHSV enables visualizing aperiodic VF vibrations. However, the technique is less well established in the clinical care of disordered voices, partly because the properties of aperiodic vibration patterns are not yet described comprehensively. To address this, a computer model for simulation of VF vibration patterns observed in a variety of different phonation types is proposed. Method: A previously published kinematic model of mucosal wave phenomena is generalized to be capable of left-right asymmetry and to simulate endoscopic videos instead of only kymograms of VF vibrations at single sagittal positions. The most influential control parameters are the glottal halfwidths, the oscillation frequencies, the amplitudes, and the phase delays. Results: The presented videos demonstrate zipper-like vibration, pressed voice, voice onset, constant and time-varying left-right and anterior-posterior phase differences, as well as left-right frequency differences of the VF vibration. Video frames, videokymograms, phonovibrograms, glottal area waveforms, and waveforms of VF contact area relating to electroglottograms are shown, as well as selected kinematic parameters. Conclusion: The presented videos demonstrate the ability to produce vibration patterns that are similar to those typically seen in endoscopic videos obtained from vocally healthy and dysphonic speakers.

The Forma Urbis Romae was a monumental marble map of ancient Rome from the Severan Dynasty. It was originally attached to the interior wall of the Temple of Peace, but through the course of the Middle Ages the marble panels of the map fell off or were deliberately removed. They have been found mainly in the vicinity of the Forum, but only about 10% of the original surface have been discovered. The wall on which the map was mounted is currently an exterior wall of the Church of SS. Cosma e Damiano, and the original holes from the iron nails used to attach the marble panels of the map are still visible on unrestored areas. In order to attempt a full reconstruction of the map from the fragments, detailed measurements of the positions of the mounting holes are required. Access to the wall itself is difficult because of its height, and surrounding construction and excavation. A method was needed to map the surface of the wall without the expense and complication of erecting scaffolding for direct hand-measurement. To this end, digital photogrammetry and gigapixel photography with a telephoto lens were combined to produce stereo-models from the street level 50 m away. From these stereo-models of merged panoramic images in excess of 200 megapixels and a Ground Sample Distance of 1 mm it was possible to use stereo-plotting to create a map of archaeologically relevant features that will serve as the foundation for determining the positions of the surviving marble pieces.

Streptococcus suis serotype 2 is an important encapsulated bacterial swine pathogen and zoonotic agent for which no effective vaccine exists. The interaction with B cells and the humoral response against S. suis are poorly understood despite their likely relevance for a potential vaccine. We evaluated germinal center (GC) B cell kinetics, as well as the production and role of S. suis-specific antibodies following infections in a mouse model. We found that mice infected with S. suis developed GC that peaked 13-21 days post-infection. GC further increased and persisted upon periodic reinfection that mimics real life conditions in swine farms. Anti-S. suis IgM and several IgG subclasses were produced, but antibodies against the S. suis capsular polysaccharide (CPS) were largely IgM. Interestingly, depletion of total IgG from the wild-type mice sera had no effect on bacterial killing by opsonophagocytosis in vitro. Somatic hypermutation and isotype switching were dispensable for controlling the infection or anti-CPS IgM production. However, T cell-deficient (Tcrb-/-) mice were unable to control bacteremia, produce optimal anti-CPS IgM titers, or elicit antibodies with opsonophagocytic activity. SAP deficiency, which prevents GC formation but not extrafollicular B cell responses, ablated anti S. suis-IgG production but maintained IgM production and eliminated the infection. In contrast, B cell deficient mice were unable to control bacteremia. Collectively, our results indicate that the antibody response plays a large role in immunity against S. suis, with GC-independent but T cell-dependent germline IgM being the major effective antibody specificities. Our results further highlight the importance IgM, and potentially anti-CPS antibodies, in clearing S. suis infections and provide insight for future development of S. suis vaccines.

Background Digital health technologies (DHTs) are promoted as means to reduce the environmental impact of healthcare systems. However, a growing literature is shedding light on the highly polluting nature of the digital industry and how it exacerbates health inequalities. Thus, the environmental footprint of DHTs should be considered when assessing their overall value to healthcare systems. The objectives of this article are to: (1) explore stakeholders’ perspectives on integrating the environmental impacts of DHTs in assessment and procurement practices; (2) identify the factors enabling or constraining the operationalisation of such a change; and (3) encourage a constructive dialogue on how environmental issues fit within healthcare systems’ push for more DHTs. Methods Semi-structured interviews were conducted with 29 stakeholders involved in DHTs in a large Canadian academic healthcare centre. Data were collected and analysed through a mixed deductive-inductive process using a framework derived from diffusion of innovations theories. Results The integration of the environmental impact of DHTs in assessment and procurement is contingent upon key micro-meso-macrosystemic factors that either enable or constrain changes in practices and processes. Innovation (micro) factors include stakeholders’ recognition of the environmental issue and the extent to which it is feasible for them to address the environmental impact of DHTs. Organisational (meso) factors include the organisation's culture, leadership, policies, and practices, as well as the expertise and professional skillsets available. Finally, external (macro) factors include political and regulatory (e.g., national strategy, laws, standards, norms), economic (e.g., business models, public procurement), and professional and scientific factors (e.g., evidence, methodologies, clinical guidelines). Conclusion Considering the environmental impact of DHTs depends on micro-meso-macrosystemic factors involving a variety of stakeholders and levels of governance, sometimes with divergent or even antagonistic objectives and expectations. It highlights the importance of better understanding the complexity inherent in the environmental shift in healthcare.

Abstract Antigen-naive IgM-producing B cells are atheroprotective, whereas mature B cells producing class-switched antibodies promote atherosclerosis. Activation-induced cytidine deaminase (AID), which mediates class switch recombination (CSR), would thus be expected to foster atherosclerosis. Yet, AID also plays a major role in the establishment of B cell tolerance. We sought to define whether AID affects atherosclerotic plaque formation. We generated Ldlr -/- chimeras transplanted with bone marrow from Aicda -/- or wild-type (WT) mice, fed a HFD for 14 weeks. Decreased B cell maturation in Ldlr -/- Aicda -/- mice was demonstrated by 50% reduction in splenic and aortic BAFFR expression, a key signaling component of B2 cell maturation. This was associated with increased plasma IgM in Ldlr –/- Aicda -/- compared with Ldlr -/- WT animals. Importantly, Ldlr -/- Aicda -/- mice had reduced atherosclerotic lesion area (0.20 ± 0.03mm2) compared with Ldlr -/- WT (0.30 ± 0.04mm2, P

Guidance is now considered not only as the selection and assignment of pupils on the basis of their grades, but also as a gradual process of building a personal project. Over the last ten years, in addition to school coaches, out-of-school actors have developed, intervening inside or outside school, on a commercial basis or not, in order to help pupils in the construction of this project. Despite their heterogeneity, both in terms of status and in terms of the actions they implement, these actors share some common characteristics – their proximity to the business world, an ambiguous relationship with school and, above all, a conception of guidance based on common presuppositions – which this article proposes to examine through an analysis of the representations they carry.

Methicillin-resistant Staphylococcus aureus (MRSA) poses significant therapeutic challenges related to its frequency in clinical infections, innate virulence properties, and propensity for multiantibiotic resistance. MRSA is among the most common causes of endovascular infections, including infective endocarditis (IE). Our objective was to employ transthoracic echocardiography (TTE) to evaluate the effect of exebacase, a novel direct lytic agent, in experimental aortic valve MRSA IE. TTE was utilized to evaluate the in vivo effect of exebacase on MRSA-infected vegetation progression when combined with daptomycin (versus daptomycin alone). Primary intravegetation outcomes were maximum size, weights at sacrifice, and MRSA counts at infection baseline versus after 4 days of daptomycin treatment (alone or in addition to exebacase administered once on treatment day 1). A single dose of exebacase in addition to daptomycin cleared significantly more intravegetation MRSA than daptomycin alone. This was associated with a statistical trend toward reduced maximum vegetation size in the exebacase plus daptomycin versus the daptomycin alone therapy groups (P = 0.07). Also, mean vegetation weights in the exebacase-treated group were significantly lower than those of the daptomycin alone group (P

Deacetylation of chitin by chitin deacetylases (Cda) results in the formation of chitosan. Chitosan, a polymer of β1,4 linked glucosamine, plays multiple roles in the function of the fungal cell wall, including virulence and evasion of host immune responses. In this study, the roles of chitosan and putative CDAs in cell wall structure and virulence of Aspergillus fumigatus were investigated. Low levels of chitosan were found in the conidial and cell wall of A. fumigatus. Seven putative CDA genes were identified, disrupted and the phenotype of the single mutants and the septuple mutants were investigated. No alterations in fungal cell wall chitosan levels, changes in fungal growth or alterations in virulence were detected in the single or septuple Δcda1-7 mutant strains. Collectively, these results suggest that chitosan is a minority component of the A. fumigatus cell wall, and that the seven candidate Cda proteins do not play major roles in fungal cell wall synthesis or virulence. However, Cda2 is involved in conidiation, suggesting that this enzyme may play a role in N-acetyl-glucosamine metabolism.

NADPH oxidase NOX2 produces superoxide, a reactive oxygen species essential in innate immunity. Here, the authors reveal the structure of the NOX2 core, rationalize disease-causing mutations, and suggest avenues for selective NOX2 pharmacological modulation.

BackgroundClinicians’ scope of responsibilities is being steadily transformed by digital health solutions that operate with or without artificial intelligence (DAI solutions). Most tools developed to foster ethical practices lack rigor and do not concurrently capture the health, social, economic, and environmental issues that such solutions raise. ObjectiveTo support clinical leadership in this field, we aimed to develop a comprehensive, valid, and reliable tool that measures the responsibility of DAI solutions by adapting the multidimensional and already validated Responsible Innovation in Health Tool. MethodsWe conducted a 3-phase mixed methods study. Relying on a scoping review of available tools, phase 1 (concept mapping) led to a preliminary version of the Responsible DAI solutions Assessment Tool. In phase 2, an international 2-round e-Delphi expert panel rated on a 5-level scale the importance, clarity, and appropriateness of the tool’s components. In phase 3, a total of 2 raters independently applied the revised tool to a sample of DAI solutions (n=25), interrater reliability was measured, and final minor changes were made to the tool. ResultsThe mapping process identified a comprehensive set of responsibility premises, screening criteria, and assessment attributes specific to DAI solutions. e-Delphi experts critically assessed these new components and provided comments to increase content validity (n=293), and after round 2, consensus was reached on 85% (22/26) of the items surveyed. Interrater agreement was substantial for a subcriterion and almost perfect for all other criteria and assessment attributes. ConclusionsThe Responsible DAI solutions Assessment Tool offers a comprehensive, valid, and reliable means of assessing the degree of responsibility of DAI solutions in health. As regulation remains limited, this forward-looking tool has the potential to change practice toward more equitable as well as economically and environmentally sustainable digital health care.

Streptococcus suis is an encapsulated bacterium causing severe diseases in swine. Here, we compared the protective properties of the capsular polysaccharide (CPS) of different S. suis serotypes by using serotype-switched mutants in a mouse model of infection. CPS structure influenced bacterial survival in mice, antibody binding, and antibody-mediated bacterial killing. The CPS of serotypes 3, 4 and 14 allowed more antibody binding and bacterial elimination than the CPS of serotypes 2, 7 and 9. Results suggest that the different CPS structures of S. suis provide varying levels of protection by influencing antigen availability and elimination by the host immune system.

Introduction: Staphylococcus aureus is the most common cause of orthopedic infections and can be challenging to treat, especially in the presence of a foreign body. The antistaphylococcal lysins exebacase and CF-296 have rapid bactericidal activity, a low propensity for resistance development, and synergize with some antibiotics. Methods: Rabbit implant-associated osteomyelitis was induced by drilling into the medial tibia followed by locally delivering exebacase, CF-296, or lysin carrier. A titanium screw colonized with methicillin-resistant S. aureus (MRSA) IDRL-6169 was inserted. Intravenous daptomycin or saline was administered and continued daily for 4 d. On day 5, rabbits were euthanized, and the tibiae and implants were collected for culture. Results were reported as log10 colony forming units (cfu) per gram of bone or log10 cfu per implant, and comparisons among the six groups were performed using the Wilcoxon rank sum test. Results: Based on implant and bone cultures, all treatments resulted in significantly lower bacterial counts than those of controls (P≤0.0025). Exebacase alone or with daptomycin as well as CF-296 with daptomycin were more active than daptomycin alone (P≤0.0098) or CF-296 alone (P≤0.0154) based on implant cultures. CF-296 with daptomycin was more active than either CF-296 alone (P=0.0040) or daptomycin alone (P=0.0098) based on bone cultures. Conclusion: Local delivery of either exebacase or CF-296 offers a promising complement to conventional antibiotics in implant-associated infections.

Abstract Inclisiran, a small interfering RNA, selectively inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis in the liver and has been shown to reduce low‐density lipoprotein cholesterol (LDL‐C) by ≥50% in patients with hypercholesterolemia receiving maximally tolerated statins. The toxicokinetic, pharmacodynamic, and safety profiles of inclisiran when coadministered with a statin were characterized in cynomolgus monkeys. Six cohorts of monkeys were administered either atorvastatin (40 mg/kg, reduced to 25 mg/kg during the study, daily, oral gavage), inclisiran (300 mg/kg every 28 days, subcutaneous administration), atorvastatin (40/25 mg/kg) and inclisiran combinations (30, 100, or 300 mg/kg), or control vehicles over 85 days followed by 90 days' recovery. Inclisiran and atorvastatin toxicokinetic parameters were similar in cohorts administered either agent alone or in combination. Inclisiran exposure increased in a dose‐proportional manner. At Day 86, atorvastatin increased plasma PCSK9 levels four‐fold from pretreatment levels but did not significantly lower serum LDL‐C levels. Inclisiran (alone or in combination) reduced PCSK9 (mean decrease 66–85%) and LDL‐C (mean decrease 65–92%) from pretreatment levels at Day 86; levels were significantly lower than the control group (p ≤ .05) and remained decreased during the 90‐day recovery. Coadministration of inclisiran with atorvastatin resulted in greater reductions in LDL‐C and total cholesterol compared with either drug alone. No toxicities or adverse effects were observed in any cohort receiving inclisiran, either alone or in combination. In summary, inclisiran significantly inhibited PCSK9 synthesis and decreased LDL‐C in cynomolgus monkeys without increasing the risk of adverse effects when coadministered with atorvastatin.

Abstract Front‐end design decisions for a process to produce sustainable aviation turbine fuel from waste materials were presented. The design employs distributed conversion of wastes to oils, which are then transported to a central facility for gasification, syngas cleaning, Fischer–Tropsch synthesis and refining, that is, a spoke‐and‐hub approach. Different aspects of the front‐end design, that is, the steps up to syngas cleaning, were evaluated. The evaluation employed a combination of case studies, calculations, experimental investigations, and literature review. The supply of sustainable aviation fuel (SAF) as a 50:50 mixture of waste‐derived and petroleum‐derived kerosene to meet the demand of an international airport (Pearson, Toronto) was employed as case study. The amount of raw material required made it impractical to make use of only one type of waste. Using the same set of assumptions, it was shown that in terms of cumulative transport distance required, a spoke‐and‐hub approach was twice as efficient as centralized processing only. Technologies for decentralized production of oils were assessed, and oils produced by pyrolysis and hydrothermal liquefaction (HTL) in pilot‐scale and larger facilities were procured and characterized. These oils were within the broader compositional space of pyrolysis oils and HTL oils reported in laboratory studies. The oil compositions were employed to study the impact of oil composition on entrained flow gasification. Thermodynamic equilibrium calculations of pyrolysis and HTL oil entrained flow gasification resulted in H2/CO ratios of syngas and O2 consumption rates in a narrow range, despite the diversity of feeds. At the same time, to produce an equal molar amount of syngas (H2 + CO), less HTL oil than pyrolysis oil was required as feed. Gas cleaning technologies were reviewed to ascertain types of contaminants anticipated after gasification, their removal effectiveness, and Fischer–Tropsch catalyst poisoning potential. Raw syngas cleaning requirements were comparable to that from coal gasification.

Voice registers are assumed to be related to different laryngeal adjustments, but objective evidence has been insufficient. While chest register is usually associated with the lower pitch range, and head register with the higher pitch range, here we investigated a professional singer who claimed an ability to produce both these registers at every pitch, throughout her entire singing range. The singer performed separated phonations alternating between the two registers (further called chest-like and head-like) at all pitches from C3 (131 Hz) to C6 (1047 Hz). We monitored the vocal fold vibrations using high-speed video endoscopy and electroglottography. The microphone sound was recorded and used for blind listening tests performed by the three authors (insiders) and by six "naive" participants (outsiders). The outsiders correctly identified the registers in 64% of the cases, and the insiders in 89% of the cases. Objective analysis revealed larger closed quotient and vertical phase differences for the chest-like register within the lower range below G4 (<392 Hz), and also a larger closed quotient at the membranous glottis within the higher range above Bb4 (>466 Hz), but not between Ab4-A4 (415-440 Hz). The normalized amplitude quotient was consistently lower in the chest-like register throughout the entire range. The results indicate that that the singer employed subtle laryngeal control mechanisms for the chest-like and head-like phonations on top of the traditionally recognized low-pitched chest and high-pitched head register phenomena. Across all pitches, the chest-like register was produced with more rapid glottal closure that was usually, but not necessarily, accompanied also by stronger adduction of membranous glottis. These register changes were not always easily perceivable by listeners, however. [ABSTRACT FROM AUTHOR]

A single crystal of ytterbium-doped “mixed” yttrium–lutetium aluminum garnet with a stoichiometric composition of (Y0.601Lu0.233Yb0.166)3Al5O12 was grown by the Czochralski method and its structure, vibronic, spectroscopic, and laser properties were studied. The stimulated-emission cross-section for Yb3+ ions was maximized to 2.53 × 10−20 cm2 at 1031 nm. The emission bandwidth was ~8 nm, and the reabsorption-free luminescence lifetime of the 2F5/2 state was 1.063 ms. Pumped at 941 nm, the Yb laser generated a maximum output power of 1.04 W at 1.03 and 1.05 μm with a high slope efficiency of 76.4% and a laser threshold of 76 mW. A continuous wavelength tuning over a range of 51.6 nm (1026.4–1078.0 nm) was also achieved. Power scaling was achieved using a 969 nm diode-pumped microchip cavity. A maximum output power of ~9 W was obtained at 1.05 μm with a slope efficiency of 76% and an almost circular laser beam profile.