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Background This study was a randomised, double-blind, placebo-controlled study intended to establish the translatability of the RLS-0071 mechanisms of action from animal disease models to humans by inhibiting neutrophil-mediated inflammation at the tissue level and major inflammatory biomarkers. We hypothesised that RLS-0071 inhibits a temporary neutrophil-mediated inflammation in the lungs induced by inhalation of low-dose lipopolysaccharide (LPS) in healthy participants. Methods Participants were randomised to one of three arms to receive inhaled LPS followed by three doses of either low-dose (10 mg·kg−1) or high-dose (120 mg·kg−1 loading dose followed by two doses of 40 mg·kg−1) RLS-0071 i.v. or placebo (saline) every 8 h. Biomarkers evaluating inflammatory responses, with absolute neutrophil counts in induced sputum as the primary end-point, were collected before and at 6 and 24 h after LPS challenge. Results Active treatment with RLS-0071 showed a similar safety profile to participants receiving placebo. RLS-0071 significantly decreased the numbers of neutrophils in sputum at 6 h post LPS by approximately half (p=0.04). Neutrophil effectors myeloperoxidase, neutrophil elastase and interleukin-1β in sputum were also significantly decreased at 6 h for RLS-0071 compared with placebo. Several biomarkers showed trends suggesting sustained decreases for RLS-0071 versus placebo at 24 h. Conclusion This clinical trial demonstrated that RLS-0071 was safe and well tolerated and modulated neutrophil-mediated inflammation in humans after inhaled LPS challenge, consistent with results from prior animal model studies.

Abstract Novel treatments are needed to reduce inflammation, improve symptoms, address exacerbations, and slow disease progression in bronchiectasis. Cathepsin C (CatC) inhibition promises to achieve this through reduction of neutrophil‐derived serine protease (including neutrophil elastase [NE] and proteinase 3 [PR3]) activation. Here, we present the phase I characterization of the novel CatC inhibitor, BI 1291583. Five phase I trials of BI 1291583 in healthy subjects are presented: a single‐rising‐dose study (NCT03414008) and two multiple‐rising‐dose studies (NCT03868540 and NCT04866160) assessing the safety, tolerability, pharmacodynamics, and pharmacokinetics of BI 1291583; a food effect study (NCT03837964); and a drug–drug interaction study (NCT03890887) of BI 1291583 and itraconazole. BI 1291583 was safe and well tolerated across the doses tested in these trials. Most adverse events (AEs) were mild or moderate in intensity, with no serious AEs, AEs of special interest or deaths reported in any trial. Drug‐related skin exfoliation was not reported more frequently in subjects treated with BI 1291583 compared with placebo. BI 1291583 was readily absorbed, and pharmacokinetics were supra‐proportional over the dose ranges assessed. Additionally, BI 1291583 inhibited CatC in a dose‐dependent manner, inhibited downstream NE activity, and decreased PR3 levels. No food effect was observed. Co‐administration of multiple doses of itraconazole increased BI 1291583 exposure approximately twofold. Due to these promising phase I results, a multinational phase II program of BI 1291583 in adults with bronchiectasis is ongoing (Airleaf™ [NCT05238675], Clairafly™ [NCT05865886], and Clairleaf™ [NCT05846230]).

Abstract Background The global research response to the COVID-19 pandemic was impressive, but also led to an infodemic and considerable research waste. Registered, but unpublished trials added to this noise. We aimed to determine the proportion of registered randomised trials of common COVID-19 treatments that were published and to describe the characteristics of these trials to examine the association between trial characteristics, publication status and research waste. Methods This meta-epidemiological cohort study used a sample of randomised trials of corticosteroids, hydroxychloroquine or vitamin D as treatments for COVID-19, registered between 1 November 2019 and 31 December 2021 and available via the WHO ICTRP portal. We searched for the trials’ published results up to 20 October 2022. We extracted the trial characteristics, analysing with descriptive statistics. We performed univariate logistic regression to examine the association between trials’ characteristics and publication status, followed by multiple logistic regression using significant characteristics to assess the association between trial characteristics and publication status. Results We identified 357 eligible trials on ICTRP. Of these, 107 (30%) had published or made their results available publicly by 20 October 2022, while 250 (70%) had not been published or shared their results publicly. Multiple logistic regression analysis showed that a larger target sample size was a significant positive predictor of publication with target sample sizes above 300 almost tripling the odds of publication (aOR: 2.75, 95% CI: 1.35 to 5.62). Conclusions Less than one third of registered trials made their results public and our findings identified that many trialists had not updated their trial registry entry with the trial status, results or both. Failure to share trial results publicly is a disservice to patients, clinicians and policy makers and adds to research waste.

Abstract Introduction The selection of inhaler device is of critical importance in chronic obstructive pulmonary disease (COPD) as the interaction between a patient’s inhalation profile and the aerosol characteristics of an inhaler can affect drug delivery and lung deposition. This study assessed the in vitro aerosol characteristics of inhaler devices approved for the treatment of COPD, including a soft mist inhaler (SMI), pressurized metered-dose inhalers (pMDIs), and dry powder inhalers (DPIs). Methods High-speed video recording was used to visualize and measure aerosol velocity and spray duration for nine different inhalers (one SMI, three pMDIs, and five DPIs), each containing dual or triple fixed-dose combinations of long-acting muscarinic receptor antagonists and long-acting β2-agonists, with or without an inhaled corticosteroid. Measurements were taken in triplicate at experimental flow rates of 30, 60, and 90 l/min. Optimal flow rates were defined based on pharmacopoeial testing requirements: 30 l/min for pMDIs and SMIs, and the rate achieving a 4-kPa pressure drop against internal inhaler resistance for DPIs. Comparison of aerosol plumes was based on the experimental flow rates closest to the optimal flow rates. Results The Respimat SMI had the slowest plume velocity (0.99 m/s) and longest spray duration (1447 ms) compared with pMDIs (velocity: 3.65–5.09 m/s; duration: 227–270 ms) and DPIs (velocity: 1.43–4.60 m/s; duration: 60–757 ms). With increasing flow rates, SMI aerosol duration was unaffected, but velocity increased (maximum 2.63 m/s), pMDI aerosol velocity and duration were unaffected, and DPI aerosol velocity tended to increase, with a more variable impact on duration. Conclusions Aerosol characteristics (velocity and duration of aerosol plume) vary by inhaler type. Plume velocity was lower and spray duration longer for the SMI compared with pMDIs and DPIs. Increasing experimental flow rate was associated with faster plume velocity for DPIs and the SMI, with no or variable impact on plume duration, whereas pMDI aerosol velocity and duration were unaffected by increasing flow rate.

Abstract Segmental instillation of lipopolysaccharide (LPS) by bronchoscopy safely induces transient airway inflammation in human lungs. This model enables investigation of pulmonary inflammatory mechanisms as well as pharmacodynamic analysis of investigational drugs. The aim of this work was to describe the transcriptomic profile of human segmental LPS challenge with contextualization to major respiratory diseases. Pre-challenge bronchoalveolar lavage (BAL) fluid and biopsies were sampled from 28 smoking, healthy participants, followed by segmental instillation of LPS and saline as control. Twenty-four hours post instillation, BAL and biopsies were collected from challenged lung segments. Total RNA of cells from BAL and biopsy samples were sequenced and analysed for differentially expressed genes (DEGs). After challenge with LPS compared with saline, 6316 DEGs were upregulated and 241 were downregulated in BAL, but only one DEG was downregulated in biopsy samples. Upregulated DEGs in BAL were related to molecular functions such as “Inflammatory response” or “chemokine receptor activity”, and upregulated pro-inflammatory pathways such as “Wnt-"/“Ras-"/“JAK-STAT” “-signaling pathway”. Furthermore, the segmental LPS challenge model resembled aspects of the five most prevalent respiratory diseases chronic obstructive pulmonary disease (COPD), asthma, pneumonia, tuberculosis and lung cancer and featured similarities with acute exacerbations in COPD (AECOPD) and community-acquired pneumonia. Overall, our study provides extensive information about the transcriptomic profile from BAL cells and mucosal biopsies following LPS challenge in healthy smokers. It expands the knowledge about the LPS challenge model providing potential overlap with respiratory diseases in general and infection-triggered respiratory insults such as AECOPD in particular.

Abstract Background Surfactant phospholipid (PL) composition plays an important role in lung diseases. We compared the PL composition of non-invasively collected exhaled breath particles (PEx) with bronchoalveolar lavage (BAL) and induced sputum (ISP) at baseline and following endotoxin (LPS) challenges. Methods PEx and BAL were collected from ten healthy nonsmoking participants before and after segmental LPS challenge. Four weeks later, PEx and ISP were sampled in the week before and after a whole lung LPS inhalation challenge. PL composition was analysed using mass spectrometry. Results The overall PL composition of BAL, ISP and PEx was similar, with PC(32:0) and PC(34:1) representing the largest fractions in all three sample types (baseline PC(32:0) geometric mean mol%: 52.1, 56.9, and 51.7, PC(34:1) mol%: 11.7, 11.9 and 11.4, respectively). Despite this similarity, PEx PL composition was more closely related to BAL than to ISP. For most lipids comparable inter-individual differences in BAL, ISP, and PEx were found. PL composition of PEx was repeatable. The most pronounced increase following segmental LPS challenge was detected for SM(d34:1) in BAL (0.24 to 0.52 mol%) and following inhalation LPS challenge in ISP (0.45 to 0.68 mol%). An increase of SM(d34:1) following segmental LPS challenge was also detectable in PEx (0.099 to 0.103 mol%). The inhalation challenge did not change PL composition of PEx. Conclusion Our data supports the peripheral origin of PEx. The lack of PL changes in PEx after inhalation challenge might to be due to the overall weaker response of inhaled LPS which primarily affects the larger airways. Compared with BAL, which always contains lining fluid from both peripheral lung and central airways, PEx analysis might add value as a selective and non-invasive method to investigate peripheral airway PL composition. Trial registration NCT03044327, first posted 07/02/2017.

Abstract Single Pulse All Optical Switching represents the ability to reverse the magnetization of a nanostructure using a femtosecond single laser pulse without any applied field. Since the first switching experiments carried out on GdFeCo ferrimagnets, this phenomena has been only recently extended to a few other materials, MnRuGa alloys and Tb/Co multilayers with a very specific range of thickness and composition. Here, we demonstrate that single pulse switching can be obtained for a large range of rare earth–transition metal multilayers, making this phenomenon much more general. Surprisingly, the threshold fluence for switching is observed to be independent of the laser pulse duration. Moreover, at high laser intensities, concentric ring domain structures are induced. These striking features contrast to those observed in Gd based materials pointing towards a different reversal mechanism. Concomitant with the demonstration of an in-plane magnetization reorientation, a precessional reversal mechanism explains all the observed features.

Increased production of Prostaglandin D2 (PGD2) is linked to development and progression of asthma and allergy. PGD2 is rapidly degraded to its metabolites, which initiate type 2 innate lymphoid cells (ILC2) migration and IL-5/IL-13 cytokine secretion in a PGD2 receptor 2 (DP2)-dependent manner. Blockade of DP2 has shown therapeutic benefit in subsets of asthma patients. Cellular mechanisms of ILC2 activity in response to PGD2 and its metabolites are still unclear. We hypothesized that ILC2 respond non-uniformly to PGD2 metabolites. ILC2s were isolated from peripheral blood of patients with atopic asthma. ILC2s were stimulated with PGD2 and four PGD2 metabolites (Δ12-PGJ2, Δ12-PGD2, 15-deoxyΔ12,14-PGD2, 9α,11β-PGF2) with or without the selective DP2 antagonist fevipiprant. Total RNA was sequenced, and differentially expressed genes (DEG) were identified by DeSeq2. Differential gene expression analysis revealed an upregulation of pro-inflammatory DEGs in ILC2s stimulated with PGD2 (14 DEGs), Δ12-PGD2 (27 DEGs), 15-deoxyΔ12,14-PGD2 (56 DEGs) and Δ12-PGJ2 (136 DEGs), but not with 9α,11β-PGF2. Common upregulated DEGs were i.e. ARG2, SLC43A2, LAYN, IGFLR1, or EPHX2. Inhibition of DP2 via fevipiprant mainly resulted in downregulation of pro-inflammatory genes such as DUSP4, SPRED2, DUSP6, ETV1, ASB2, CD38, ADGRG1, DDIT4, TRPM2, or CD69. DEGs were related to migration and various immune response-relevant pathways such as "chemokine (C-C motif) ligand 4 production", "cell migration", "interleukin-13 production", "regulation of receptor signaling pathway via JAK-STAT", or "lymphocyte apoptotic process", underlining the pro-inflammatory effects of PGD2 metabolite-induced immune responses in ILC2s as well as the anti-inflammatory effects of DP2 inhibition via fevipiprant. Furthermore, PGD2 and metabolites showed distinct profiles in ILC2 activation. Overall, these results expand our understanding of DP2 initiated ILC2 activity.

Abstract Background For the professions of audiology and speech-language therapy (A/SLT), there continues be a dire need for more equitable services. Therefore there is a need to develop emerging practices which have a specific focus on equity as a driving force in shifting practices. This scoping review aimed to synthesise the characteristics of emerging practices in A/SLT clinical practice in relation to equity with an emphasis on communication professions. Methods This scoping review followed the Joanna Briggs Institute guidelines and aimed to map the emerging practices in A/SLT to identify the ways in which the professions are developing equitable practices. Papers were included if they addressed equity, focused on clinical practice and were situated within A/SLT literature. There were no time or language restrictions. The review included all sources of evidence across PubMed, Scopus, EbscoHost, The Cochrane Library and Dissertation Abstracts International, Education Resource Information Centre from their inception. The review uses PRISMA Extension for scoping reviews and PRISMA-Equity Extension reporting guidelines. Results The 20 included studies ranged from 1997–2020, spanning over 20 years. There were a variety of papers including empirical studies, commentaries, reviews and research. The results demonstrated that the professions were increasingly considering addressing equity through their practice. However, there was a prominent focus around culturally and linguistically diverse populations, with limited engagement around other intersections of marginalisation. The results also showed that while the majority of contributions to theorising equity are from the Global North with a small cluster from the Global South offering critical contributions considering social categories such as race and class. Collectively the contributions from the Global South remain a very small minority of the professional discourse which have a focus on equity. Conclusion Over the last eight years, the A/SLT professions are increasingly developing emerging practices to advance equity by engaging with marginalised communities. However, the professions have a long way to go to achieve equitable practice. The decolonial lens acknowledges the impact and influence of colonisation and coloniality in shaping inequity. Using this lens, we argue for the need to consider communication as a key aspect of health necessary to achieve health equity.

The success of clinical trials of selective B-cell depletion in patients with relapsing multiple sclerosis (MS) and primary progressive MS has led to a conceptual shift in the understanding of MS pathogenesis, away from the classical model in which T cells were the sole central actors and toward a more complex paradigm with B cells having an essential role in both the inflammatory and neurodegenerative components of the disease process. The role of B cells in MS was selected as the topic of the 27th Annual Meeting of the European Charcot Foundation. Results of the meeting are presented in this concise review, which recaps current concepts underlying the biology and therapeutic rationale behind B-cell-directed therapeutics in MS, and proposes strategies to optimize the use of existing anti-B-cell treatments and provide future directions for research in this area. ANN NEUROL 2021;89:13-23.

The development of approaches that can efficiently control the magnetization of magnetic materials is central to the creation of fast and low-power spintronic devices. Spin transfer torque can be used to electrically manipulate magnetic order in devices, but is typically limited to nanosecond timescales. Alternatively, spin–orbit torque can be employed, and switching with current pulses down to ~200 ps has been demonstrated. However, the upper limit to magnetization switching speed remains unestablished. Here, we show that photoconductive switches can be used to apply 6-ps-wide electrical pulses and deterministically switch the out-of-plane magnetization of a common thin cobalt film via spin–orbit torque. We probe the ultrafast magnetization dynamics due to spin–orbit torques with sub-picosecond resolution using the time-resolved magneto-optical Kerr effect (MOKE). We also estimate that the magnetization switching consumes less than 50 pJ in micrometre-sized devices.

This paper delves into the application of vibration-based energy harvesting to power environmental sensor nodes, a critical component of modern data collection systems. These sensor nodes play a crucial role in structural health monitoring, providing essential data on external conditions that can affect the health and performance of structures. We investigate the feasibility and efficiency of utilizing piezoelectric vibration energy harvesters to sustainably power environmental wireless sensor nodes on the one hand. On the other hand, we exploit different approaches to minimize the sensor node’s power consumption and maximize its efficiency. The investigations consider various sensor node platforms and assess their performance under different voltage levels and broadcast frequencies. The findings reveal that optimized harvester designs enable real-time data broadcasting with short intervals, ranging from 1 to 3 s, expanding the horizons of environmental monitoring, and show that in case the system includes a battery as a backup plan, the battery’s lifetime can be extended up to 9 times. This work underscores the potential of vibration energy harvesting as a viable solution for powering sensor nodes, enhancing their autonomy, and reducing maintenance costs in remote and challenging environments. It opens doors to broader applications of sustainable energy sources in environmental monitoring and data collection systems.

Under laser illumination it is possible to drive a ferromagnet to lose its magnetization. While this process can be rapid, remagnetization following this is slower, due to the universal critical slowing down near the phase transition. Here, Remy et al show how such a slowing down can be overcome, changing the direction of magnetization in 400 femtoseconds.

Abstract Background Noncommunicable diseases are major contributors to morbidity and mortality worldwide. Modifying the risk factors for these conditions, such as physical inactivity, is thus essential. Addressing the context or circumstances in which physical activity occurs may promote physical activity at a population level. We assessed the effects of infrastructure, policy or regulatory interventions for increasing physical activity. Methods We searched PubMed, Embase and clinicaltrials.gov to identify randomised controlled trials (RCTs), controlled before-after (CBAs) studies, and interrupted time series (ITS) studies assessing population-level infrastructure or policy and regulatory interventions to increase physical activity. We were interested in the effects of these interventions on physical activity, body weight and related measures, blood pressure, and CVD and type 2 diabetes morbidity and mortality, and on other secondary outcomes. Screening and data extraction was done in duplicate, with risk of bias was using an adapted Cochrane risk of bias tool. Due to high levels of heterogeneity, we synthesised the evidence based on effect direction. Results We included 33 studies, mostly conducted in high-income countries. Of these, 13 assessed infrastructure changes to green or other spaces to promote physical activity and 18 infrastructure changes to promote active transport. The effects of identified interventions on physical activity, body weight and blood pressure varied across studies (very low certainty evidence); thus, we remain very uncertain about the effects of these interventions. Two studies assessed the effects of policy and regulatory interventions; one provided free access to physical activity facilities and showed that it may have beneficial effects on physical activity (low certainty evidence). The other provided free bus travel for youth, with intervention effects varying across studies (very low certainty evidence). Conclusions Evidence from 33 studies assessing infrastructure, policy and regulatory interventions for increasing physical activity showed varying results. The certainty of the evidence was mostly very low, due to study designs included and inconsistent findings between studies. Despite this drawback, the evidence indicates that providing access to physical activity facilities may be beneficial; however this finding is based on only one study. Implementation of these interventions requires full consideration of contextual factors, especially in low resource settings. Trial registration PROSPERO 2018 CRD42018093429.

Historical dog training methods reveal that dog training then and now might not have been that different. While some methods that would be considered unacceptable today have vanished over time, much of what we do today has been practiced historically for a long time. Albertus Magnus’ De animalibus and Petrus de Crescentiis’ Ruralia commodia deliver us historical evidence on how dogs were perceived, kept and trained by our ancestors. Not only were they already kept as pets, but they were also used in a wide range of professions. Dogs were utilized as guard and watchdogs, for hunting and for herding and livestock protection. Dogs are still trained in many of those professions today. From these historical records, we can learn how the perception and use of dogs has been similar or very different from our view on dogs today. We see how certain training methods have persisted over time, giving us an opportunity to ponder on new training and handling methods for man’s best friend.

Abstract Thromboembolism is frequent in infective endocarditis (IE). However, the optimal antithrombotic regimen in IE is unknown. Staphylococcus aureus (SA) is the leading cause of IE. First studies emphasize increased platelet reactivity by SA. In this pilot study, we hypothesized that platelet reactivity is increased in patients with SA− IE, which could be abrogated by antiplatelet medication. We conducted a prospective, observatory, single-center cohort study in 114 patients with IE, with four cohorts: (1) SA coagulase positive IE without aspirin (ASA) medication, (2) coagulase negative IE without ASA, (3) SA coagulase positive IE with ASA, (4) coagulase negative IE with ASA. Platelet function was measured by Multiplate electrode aggregometry, blood clotting by ROTEM thromboelastometry. Bleeding events were assessed according to TIMI classification. In ASA-naïve patients, aggregation with ADP was increased with coag. pos. IE (coagulase negative: 39.47 ± 4.13 AUC vs. coagulase positive: 59.46 ± 8.19 AUC, p = 0.0219). This was abrogated with ASA medication (coagulase negative: 42.4 ± 4.67 AUC vs. coagulase positive: 45.11 ± 6.063 AUC p = 0.7824). Aspirin did not increase bleeding in SA positive patients. However, in SA negative patients with aspirin, red blood cell transfusions were enhanced. SA coagulase positive IE is associated with increased platelet reactivity. This could be abrogated by aspirin without increased bleeding risk. The results of this pilot study suggest that ASA might be beneficial in SA coagulase positive IE. This needs to be confirmed in clinical trials.

Abstract The impact of plasmonic surface lattice resonances on the magneto‐optical properties and energy absorption efficiency has been studied in arrays of [Co/Gd/Pt]N multilayer nanodisks. Varying the light wavelength, the disk diameter, and the period of the array, it is demonstrated that surface lattice resonances allow all‐optical single pulse switching of [Co/Gd/Pt]N nanodisk arrays with an energy 400% smaller than the energy needed to switch a continuous [Co/Gd/Pt]N film. Moreover, the magneto‐optical Faraday effect is enhanced at the resonance condition by up to 5,000%. The influence of the disk diameter and array period on the amplitude, width and position of the surface lattice resonances is in qualitative agreement with theoretical calculations and opens the way to designing magnetic metasurfaces for all‐optical magnetization switching applications.