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Abstract The synthesis of a family of chiral and enantiomerically pure pyridyl‐diamide (pda) ligands that upon complexation with europium [Eu(CF3SO3)3] result in chiral complexes with metal centered luminescence is reported; the sets of enantiomers giving rise to both circular dichroism (CD) and circularly polarized luminescence (CPL) signatures. The solid‐state structures of these chiral metallosupramolecular systems are determined using X‐ray diffraction showing that the ligand chirality is transferred from solution to the solid state. This optically favorable helical packing arrangement is confirmed by recording the CPL spectra from the crystalline assembly by using steady state and enantioselective differential chiral contrast (EDCC) CPL Laser Scanning Confocal Microscopy (CPL‐LSCM) where the two enantiomers can be clearly distinguished.

Despite their high brightness and long-lived emission, lanthanide based circularly polarised luminophores have not been fully exploited for real-life application. Here, the authors present an all solid-state circularly polarised luminescence camera to facilitate ad hoc time-resolved enantioselective differential chiral contrast-based one-shot photography that can be applied in life and material sciences.

Here, the authors introduce a live-cell imaging system using chiroptical contrast, enabling the study of chiral interactions. They demonstrate simultaneous imaging of enantiomeric pairs of molecular probes emitting circularly polarised light, using both single and two-photon excitation.

Lanthanide-based supramolecular complexes have labile and hard-topredict chemical structures. Here the authors show controlled formation of either helicates or tetrahedron shaped cages based on the interplay between the metal ionic radius and the ligand composition.

Circular polarization luminescence (CPL) spectroscopy is a tool to study chiroptical systems, but the measurement process is generally very slow. The authors introduce a CPL technique with much faster acquisition, demonstrating meaningful time-dependent measurements and enabling new applications.

Cubic (α-phase) NaYF4:Yb,Er upconversion nanoparticles (UCNPs) are uniquely suited to biophotonics and biosensing applications due to their near-infrared excitation and visible red emission (λex approx. 660 nm), enabling detection via thick overlying tissue with no bio-autofluorescence. However, UCNP synthesis typically requires high temperatures in combination with either high pressure reaction vessels or an inert atmosphere. Here, we report synthesis of α-phase NaYF4:Yb,Er,Mn UCNPs via the considerably more convenient PVP40-mediated route; a strategy that requires modest temperatures and relatively short reaction time (160°C, 2 h) in open air, with Mn2+ co-doping serving to greatly enhance red emission. The optimal Mn2+ co-doping level was found to be 35 mol %, which decreased the average maximum UCNP Feret diameter from 42 ± 11 to 36 ± 15 nm; reduced the crystal lattice parameter, a, from 5.52 to 5.45 Å; and greatly enhanced UCNP red/green emission ratio in EtOH by a factor of 5.6. The PVP40 coating enabled dispersal in water and organic solvents and can be exploited for further surface modification (e.g. silica shell formation). We anticipate that this straightforward UCNP synthesis method for producing strongly red-emitting UCNPs will be particularly beneficial for deep tissue biophotonics and biosensing applications.

A new method for facilitating the delivery, uptake and intracellular localisation of thermally activated delayed fluorescence (TADF) complexes was developed. First, confinement of TADF complexes in liposomes was demonstrated, which were subsequently used as the delivery vehicle for cellular uptake. Confocal fluorescence microscopy showed TADF complexes subsequently localise in the cytoplasm of HepG2 cells. The procedures developed in this work included the removal of molecular oxygen in the liposome preparation without disrupting the liposome structures. Time-resolved fluorescence microscopy (point scanning) showed initial prompt fluorescence followed by a weak, but detectable, delayed fluorescence component for liposomal TADF internalised in HepG2 cells. By demonstrating that it is possible to deliver un-functionalised and/or unshielded TADF complexes, a sensing function for TADFs, such as molecular oxygen, can be envisaged.

Controlling the chirality of self-assembled polyhedra is a synthetic challenge. Here, the authors stereoselectively form emissive lanthanide tetrahedral cages from a series of chiral ligands, and use their circularly polarized luminescence to explore the effect of ligand point chirality on supramolecular architecture.

The histone deacetylase (HDAC) enzymes have emerged as an important class of molecular targets in cancer therapy, with five inhibitors in clinical use. Recently, it has been shown that a lack of selectivity between the 11 Zn-dependent HDAC isoforms may lead to unwanted side-effects. In this paper, we show that piano stool Ru complexes can act as HDAC inhibitors, and variation in the capping arene leads to differences in HDAC isoform selectivity.

Structured illumination microscopy is a super-resolution technique used extensively in biological research. However, this technique is limited in the maximum possible resolution increase. Here we report the results of simulations of a novel enhanced multi-spot structured illumination technique. This method combines the super-resolution technique of difference microscopy with structured illumination deconvolution. Initial results give at minimum a 1.4-fold increase in resolution over conventional structured illumination in a low-noise environment. This new technique also has the potential to be expanded to further enhance axial resolution with three-dimensional difference microscopy. The requirement for precise pattern determination in this technique also led to the development of a new pattern estimation algorithm which proved more efficient and reliable than other methods tested.

Abstract Light-chain (LC) monoclonal gammopathy of undetermined significance (MGUS) is a precursor of multiple myeloma (MM) and related conditions. LC-MGUS is characterized by free light-chain (FLC) levels outside defined reference intervals, indirectly indicating underlying plasma cell (PC) monoclonality. Next-generation flow cytometry (NGF) was used to evaluate clonal PC presence in bone marrow (BM) samples from individuals with LC-MGUS in the iStopMM study, aiming to assess the predictive value of the FLC ratio for clonal PC presence and its prognostic implications. BM samples from 61 individuals with LC monoclonal gammopathy were analyzed. Clonal plasma cells were detected in 53.6% of LC-MGUS samples (n = 28) and in all samples from individuals with more advanced conditions (n = 33). The FLC ratio was predictive of clonal PC presence for kappa-involved FLC ratios (p 1.65 to 3.15 progressed to MM (n = 124), whereas 4/71 (5.6%) with FLC ratios >3.15 progressed over median follow-up of 55 months. These findings support using a kappa-involved FLC ratio cutoff of >3.15 to more accurately identify individuals at increased risk of developing symptomatic PC disorders.

Abstract Although aging clocks predicting the age of individual organisms have been extensively studied, the age of individual cells remained largely unexplored. Most recently single-cell omics clocks were developed for the mouse, however, extensive profiling the age of human cells is still lacking. To fill this gap, here we use available scRNA-seq data of 1,058,909 blood cells of 508 healthy, human donors (between 19 and 75 years), for developing single-cell transcriptomic clocks and predicting the age of human blood cells. By the application of the proposed cell-type-specific single-cell clocks, our main observations are that (i) transcriptomic age is associated with cellular senescence; (ii) the transcriptomic age of classical monocytes as well as naive B and T cells is decreased in moderate COVID-19 followed by an increase for some cell types in severe COVID-19; and (iii) the human embryo cells transcriptomically rejuvenated at the morulae and blastocyst stages. In summary, here we demonstrate that single-cell transcriptomic clocks are useful tools to investigate aging and rejuvenation at the single-cell level.

AbstractBackground/Objectives There is a great unmet need for accessible adjunctive interventions to promote long-term recovery from substance use disorder (SUD). This study aimed to iteratively develop and test the initial feasibility and acceptability of Mindful Journey, a novel digital mindfulness-based intervention for promoting recovery among individuals with SUD.Patients/Materials Ten adults receiving outpatient treatment for SUD.Methods Phase 1 (n = 5) involved developing and testing a single introductory digital lesson. Phase 2 included a separate sample (n = 5) and involved testing all 15 digital lessons (each 30- to 45-minutes) over a 6-week period, while also receiving weekly brief phone coaching for motivational/technical support.Results Across both phases, quantitative ratings (rated on a 5-point scale) were all at or above a 4 (corresponding with ‘agree’) for key acceptability dimensions, such as usability, understandability, appeal of visual content, how engaging the content was, and helpfulness for recovery. Additionally, in both phases, qualitative feedback indicated that participants particularly appreciated the BOAT (Breath, Observe, Accept, Take a Moment) tool for breaking down mindfulness into steps. Qualitative feedback was used to iteratively refine the intervention. For example, based on feedback, we added a second core mindfulness tool, the SOAK (Stop, Observe, Appreciate, Keep Curious), and we added more example clients and group therapy videos. In Phase 2, 4 out of 5 participants completed all 15 lessons, providing initial evidence of feasibility. Participants reported that the phone coaching motivated them to use the app. The final version of Mindful Journey was a smartphone app with additional features, including brief on-the-go audio exercises and a library of mindfulness practices. Although, participants used these additional features infrequently.Conclusions Based on promising initial findings, future acceptability and feasibility testing in a larger sample is warranted. Future versions might include push notifications to facilitate engagement in the additional app features.

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is the precursor of multiple myeloma (MM) and related disorders. MGUS is characterized by asymptomatic paraproteinemia. In some cases, multiple paraproteins can be identified but the clinical implications of this phenomenon are poorly understood. In this study, we aim to inform the approach to this challenging MGUS subgroup by utilizing data from iStopMM, a population‐based screening study and randomized trial of follow‐up strategies. In total, 75,422 Icelanders over the age of 40 were screened for MGUS with 3389 (4.4%) having at least one paraprotein of whom 303 (9%) had multiple paraproteins. IgM paraproteins were more common in those with multiple paraproteins (49% vs. 27% of paraproteins, p

El Reemplazo Articular total es un recurso terapeútlco valioso pero conlleva el riesgo de infectarse en el 1 % de los casos. Presentamos dos casos de prótesis Articulares Infectadas atendidos en el C.M.N entre 1990-1991. CASO 1 : MGA 68a, mujer, con coxartrosis IV, se le efectuó artroplastía con prótesis no-cementada. Desde P09 evidencia sígnos flogósicos, fiebre ondulante. Ex. Auxiliares: Hemograma:N Hemocultivos:Neg. Urocultivo:Neg. Rx. Torax:N. Rx Pelvis: Zonas osteolíticas en región del trocanter mayor que se propaga hacia canal medular. Cultivo de punción-aspiración de herida operatoria Pseudomona au. Tratamiento:Ciprofloxacina. Alta voluntaria. CASO 2 : AAL 78a, mujer, sometida a artroplastía en 1989 por coxartrosis IV derecha. Un año después inicia con dolor en coxoíemoral derecha,Cebrículas y flogósis en región trocantérea.Ex. Aux:Hemograma: N, Rx pelvis: erosiones y periostitis.Tratamiento inicial Cue remoción de prótesis, lavado y reimplante de la misma prótesis, 6 meses después desarrolla f'astula sometiéndosele a cura quirúrgica de osteomielitis e irrigación continua. Cultivo de secreción de lecho operatorio: Acinetobacter. Los casos descritos tuvieron diferentes mecanismos de infección de partes blandas que por contiguidad contaminó la prótesis y el segundo caso una infección a distancia con bacteremia y posterior colonización en prótesis.

Abstract Introduction Intra-oral halitosis (IOH) is the most common type of bad breath; its consequences impair quality of life. However, evidence-based treatment protocols and guidelines are lacking. Our aim is to investigate the effectiveness of chlorine dioxide as an applicable complementary treatment modality in IOH after tongue cleaning. Methods and analysis The ODOR trial will be a single-center, double-blinded, parallel-group, double-armed pilot randomized controlled trial with a non-inferiority design. The efficacy of hyperpure chlorine dioxide will be compared to chlorhexidine mouthwash. We plan to investigate the short-term effects of the intervention over a 3-h period. The primary endpoint will be changes in organoleptic test scores. At the end of the pilot investigation of the first 30 patients each, sample size calculation will be performed. If feasible, the investigators will continue the study by enrolling more patients. Trial registration The trial has been registered at ClinicalTrials.gov (NCT06219226).

Abstract Sociodemographic and lifestyle factors (sleep, physical activity, and sedentary behavior) may predict obesity risk in early adolescence; a critical period during the life course. Analyzing data from 2971 participants (M = 11.94, SD = 0.64 years) wearing Fitbit Charge HR 2 devices in the Adolescent Brain Cognitive Development (ABCD) Study, glass box machine learning models identified obesity predictors from Fitbit-derived measures of sleep, cardiovascular fitness, and sociodemographic status. Key predictors of obesity include identifying as Non-White race, low household income, later bedtime, short sleep duration, variable sleep timing, low daily step counts, and high heart rates (AUCMean = 0.726). Findings highlight the importance of inadequate sleep, physical inactivity, and socioeconomic disparities, for obesity risk. Results also show the clinical applicability of wearables for continuous monitoring of sleep and cardiovascular fitness in adolescents. Identifying the tipping points in the predictors of obesity risk can inform interventions and treatment strategies to reduce obesity rates in adolescents.

The aim of this work is to explore the possibility of using a magnetic ionic liquid as both a lubricant and sealant in a vacuum pump. The current lubricant in use is due to become obsolete due to incoming legislation on fluorinated compounds. The long-term goal is to use a magnetic field to hold the novel lubricant in place to create a better seal and thus reduce pressure more effectively whilst also lubricating the necessary mechanical parts. This paper explores physical properties (contact angle, viscosity, coefficient of friction (COF) and magnetism) and chemical properties (thermal stability and chemical stability as deduced by X-ray photoelectron spectroscopy (XPS)) of three ionic liquids based on imidazolium cations with varying length of alkyl side chain and a tetrachloroferrate anion along with two control lubricants which are used currently in the field and based upon perfluoropolyether (PFPE). The work shows that the three magnetic ionic liquids possess a lower COF value than the two control lubricants when measured using a Bruker UMT TriboLab suggesting they may perform better in the real life vacuum pump. Upon analysis of the three ionic liquid samples after tribological testing using XPS, it was shown that the ionic liquid samples displayed minor differences in spectra suggesting good stability with no obvious decomposition or degradation of the sample.

To improve the microstructure and mechanical properties of heat-resistant 12Kh1MF steel after long-term operation in the stretched bend zone of the main steam pipeline of a thermal power plant, restorative heat treatment (RHT) was proposed. The RHT mode consisted of two normalization stages (from temperatures of 1100 and 960 °C, respectively) followed by tempering at a temperature of 740 °C. The RHT mode, regulated for steel in the initial state, was applied only after its normalization from a significantly higher temperature (1100 °C). It was shown that the proportion of fine grains in the steel structure increased to 55% over the entire pipe wall thickness after using RHT. At the same time, the proportion of large grains in the restored steel decreased significantly (to 10%), while in exploited steel, their proportion reached almost 50%. The proposed RHT mode increased the hardness, strength, plasticity, and resistance to brittle fracture of the restored steel relative to the corresponding characteristics of the operated steel. The maximum positive effect of the RHT was obtained during impact testing. The fractographic features of the exploited and restored steel were studied on fractures of samples tested by tension. The main fractographic feature of the operated steel was nanosized particles at the bottom of large dimples. These tiny particles were considered to be fragments of large carbides formed due to their final decohesion from the matrix during tensile testing. However, such nanosized particles were not found on the samples’ fracture surfaces in the steel after restorative heat treatment. In addition, the ductile dimples on the fractures of the restored steel were more prominent, which indicated high energy costs for their formation. Thus, all the obtained research results suggest the possibility of using the proposed RHT mode to extend the service life of long-operated critical elements of a thermal power plant’s steam pipelines.

Abstract Hemodilution of bone marrow (BM) aspirates is a limitation of multiparameter flow cytometry (MFC) in plasma cell disorders. There is a need for a validated approach for assessing sample quality and the distribution of non-plasma cell BM populations by MFC could provide a solution. We evaluated BM-associated cell populations, assessed by next-generation flow cytometry (NGF) and white blood cell (WBC) count in 351 BM aspirated samples from 219 participants with plasma cell disorders in the Iceland Screens, Treats, or Prevents MM study (iStopMM), as markers of hemodilution by their discriminatory ability between first and (generally more hemodiluted) second pull BM aspirated samples. The most discriminating markers were used to derive a novel BM quality index (BMQI). Nucleated red blood cells and myeloid precursors provided the greatest discriminatory ability between first vs second pull samples (area under the curve (AUC): 0.87 and 0.85, respectively), significantly better than B cell precursors (AUC = 0.64; p

Abstract Cyclosporine-A (CsA) is used to prevent acute graft-versus-host disease (aGvHD). European Society for Blood and Marrow transplantation (EBMT) recommends a CsA target serum concentration of 200–300 µg/L during the first month after allogeneic hematopoietic stem cell transplantation (HSCT). With this study, we investigated whether a median CsA concentration > 200 µg/L (CsAhigh) the first month after HSCT, compared to ≤ 200 µg/L (CsAlow), increased the relapse risk of acute myloid leukemia (AML), using unrelated donors (URD) and antithymocyte globulin (ATG). Data was collected from 157 patients with AML, transplanted 2010–2016. The cumulative incidence of relapse (CIR) at 60 months was 50% in the CsAhigh versus 32% in the CsAlow group (p = 0.016). In univariate analysis, CsAhigh versus CsAlow (p = 0.028), 10-unit increase of CsA as a continuous variable (p = 0.017) and high risk disease (p = 0.003) were associated with higher CIR. The results remained after adjusting for disease risk. Death following relapse occurred more frequently in the CsAhigh group (p = 0.0076). There were no significant differences in rates of aGvHD, chronic GvHD (cGvHD), EBV/CMV-infections or overall survival (OS) between the two groups. In conclusion, we found that a median CsA concentration > 200 µg/L, the first month after HSCT, results in higher CIR of AML when combined with ATG.

Abstract We aimed to elucidate the effects of “dose” of a single-session of mindfulness meditation on state mindfulness and affect as well as moderators of effects. 372 adults recruited remotely via Amazon’s MTurk platform were randomly assigned to either a: 10-min mindfulness meditation, 20-min mindfulness meditation, 10-min control, or 20-min control. Control conditions were recordings of a National Geographic article. Primary outcomes were changes in state mindfulness, anxiety, and negative and positive affect. Moderator variables included neuroticism, trait mindfulness, and prior meditation experience. Collapsing across doses, participants in mindfulness conditions reported greater increases in state mindfulness than in control conditions. There was a greater increase in state mindfulness in the 10-min mindfulness condition versus 10-min control condition. There were no differences between 10- and 20-min mindfulness conditions. Exploratory moderation analyses indicated that meditation (10 or 20) versus control (10 or 20) predicted increased state mindfulness among participants with lower trait mindfulness. Additionally, 20-min versus 10-min meditation predicted greater decreases in state anxiety among individuals with high trait mindfulness. Dose–response relationships were minimal, suggesting that 10 and 20 min of meditation may improve state mindfulness comparably. Findings support the benefits of brief mindfulness meditation and suggest that trait mindfulness moderates certain outcomes.

Objective and importance of the study: In Australia, preventable causes of morbidity and mortality are common among men. The National Men’s Health Strategy 2021–2030 highlights the need to successfully engage men in disease prevention; hence, we aimed to examine the prevention priorities, attitudes and information sources reported by Australian men. Study type: Population survey. Methods: Men aged 18 years and over were recruited from the nationally representative Life in Australia panel. Participants completed an online survey that measured the prevention issues of greatest concern, attitudes to prevention behaviours and services, and the health information sources considered most useful. Results: Among 1282 respondents, mental health issues, followed by those pertaining to chronic disease and relationships, were rated of highest concern. Weight management, physical activity, and fruit and vegetable consumption were most often considered as important for personal health. Being 65 years and older and having adequate health literacy were strongly associated with positive attitudes towards prevention practices. More than three-quarters of men rated their doctor as the most useful information source, followed by health websites, internet searching, and their partner. Conclusions: Psychological and social issues are of high concern to men, and their attitudes toward preventive behaviours and services often do not align with public health recommendations. Understanding the topics of greatest concern to men and their preferred sources of information can inform communication and engagement strategies to improve health-related practices among men.

X-ray photoelectron spectroscopy (XPS) analysis of cerium is ubiquitous amongst the catalytic and materials literature however errors in experimental procedure and data analysis are often easily proliferated. In this work we focus on the best practice for experimental construction when approaching the task of understanding chemical environments in cerium-based materials by XPS.

Abstract In recent years, research on methods for locating a source of spreading phenomena in complex networks has seen numerous advances. Such methods can be applied not only to searching for the “patient zero” in epidemics, but also finding the true sources of false or malicious messages circulating in the online social networks. Many methods for solving this problem have been established and tested in various circumstances. Yet, we still lack reviews that would include a direct comparison of efficiency of these methods. In this paper, we provide a thorough comparison of several observer-based methods for source localisation on complex networks. All methods use information about the exact time of spread arrival at a pre-selected group of vertices called observers. We investigate how the precision of the studied methods depends on the network topology, density of observers, infection rate, and observers’ placement strategy. The direct comparison between methods allows for an informed choice of the methods for applications or further research. We find that the Pearson correlation based method and the method based on the analysis of multiple paths are the most effective in networks with synthetic or real topologies. The former method dominates when the infection rate is low; otherwise, the latter method takes over.

Abstract Home‐based measures of lung function, inflammation, symptoms, and medication use are frequently collected in respiratory clinical trials. However, new statistical approaches are needed to make better use of the information contained in these data‐rich variables. In this work, we use data from two phase III asthma clinical trials demonstrating the benefit of benralizumab treatment to develop a novel longitudinal mixed effects model of peak expiratory flow (PEF), a lung function measure easily captured at home using a hand‐held device. The model is based on an extension of the mixed effects modeling framework to incorporate stochastic differential equations and allows for quantification of several statistical properties of a patient's PEF data: the longitudinal trend, long‐term fluctuations, and day‐to‐day variability. These properties are compared between treatment groups and related to a patient's exacerbation risk using a repeated time‐to‐event model. The mixed effects model adequately described the observed data from the two clinical trials, and model parameters were accurately estimated. Benralizumab treatment was shown to improve a patient's average PEF level and reduce long‐term fluctuations. Both of these effects were shown to be associated with a lower exacerbation risk. The day‐to‐day variability was neither significantly affected by treatment nor associated with exacerbation risk. Our work shows the potential of a stochastic model‐based analysis of home‐based lung function measures to support better estimation and understanding of treatment effects and disease stability. The proposed analysis can serve as a complement to descriptive statistics of home‐based measures in the reporting of respiratory clinical trials.

Abstract In this paper we analyze the effect of shocks in production networks. Our work is based on a rich dataset that contains information about companies from Slovenia right after the financial crisis of 2008. The processed data spans for 8 years and covers the transaction history as well as performance indicators and various metadata of the companies. We define sales shocks at different levels, and identify companies impacted by them. Next we investigate stress, the potential immediate upstream and downstream impact of a shock within the production network. We base our main findings on a matched pairs analysis of stressed companies. We find that both shock and stress are associated with reporting bankruptcy in the future and that stress foremost impacts the future sales of customers. Furthermore, we find evidence that stress not only results in performance losses but the reconfiguration of the production network as well. We show that stressed companies actively seek for new trading partners, and that these new links often share the industry of the shocked company. These results suggest that both stressed customers and suppliers react quickly to stress and adjust their trading relationships.

Additive Manufacturing (AM) is an advanced technology that has been primarily driven by the demand for production efficiency, minimized energy consumption, and reduced carbon footprints. This process involves layer-by-layer material deposition based on a Computer-Aided Design (CAD) model. Compared to traditional manufacturing methods, AM has enabled the development of complex and topologically functional geometries for various service parts in record time. However, there are limitations to mass production, the building rate, the build size, and the surface quality when using metal additive manufacturing. To overcome these limitations, the combination of additive manufacturing with traditional techniques such as milling and casting holds the potential to provide novel manufacturing solutions, enabling mass production, improved geometrical features, enhanced accuracy, and damage repair through net-shape construction. This amalgamation is commonly referred to as hybrid manufacturing or multi-material additive manufacturing. This review paper aimed to explore the processes and complexities in hybrid materials, joining techniques, with a focus on maraging steels. The discussion is based on existing literature and focuses on three distinct joining methods: direct joining, gradient path joining, and intermediate section joining. Additionally, current challenges for the development of the ideal heat treatment for hybrid metals are discussed, and future prospects of hybrid additive manufacturing are also covered.

Abstract Background Infection and graft-versus-host disease (GvHD) are the major causes for mortality and morbidity of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Plasma-derived extracellular vesicles (EVs) contain disease-related proteins, DNAs and RNAs, and have recently been suggested as potential biomarker candidates for transplantation complications. However, EV isolation from small plasma volumes in clinical biomarker studies using conventional methods is challenging. We therefore investigated if EVs isolated by novel automated acoustic trapping could be developed as potential biomarkers for allo-HSCT complications by performing a clinical proof-of-principle study. Results Plasma samples were collected from twenty consecutive patients with high-risk/relapsed hematologic malignancies undergoing allo-HSCT before transplantation and post-transplant up to 12 weeks. EVs were isolated from small plasma sample volumes (150 μl) by an automated, acoustofluidic-based particle trapping device, which utilizes a local λ/2 ultrasonic standing wave in a borosilicate glass capillary to capture plasma EVs among pre-seeded polystyrene microbeads through sound scatter interactions. We found that EVs could be reliably isolated from all plasma samples (n = 173) and that EV numbers increased more than 2-fold in the majority of patients after transplantation. Also, sufficient quantities of RNA for downstream microRNA (miRNA) analysis were obtained from all samples and EV miRNA profiles were found to differ from whole plasma profiles. As a proof of principle, expression of platelet-specific miR-142-3p in EVs was shown to correlate with platelet count kinetics after transplantation as expected. Importantly, we identified plasma EV miRNAs that were consistently positively correlated with infection and GvHD, respectively, as well as miRNAs that were consistently negatively correlated with these complications. Conclusions This study demonstrates that acoustic enrichment of EVs in a clinical biomarker study setting is feasible and that downstream analysis of acoustically-enriched EVs presents a promising tool for biomarker development in allo-HSCT. Certainly, these findings warrant further exploration in larger studies, which will have significant implications not only for biomarker studies in transplantation but also for the broad field of EV-based biomarker discovery.

Abstract Background Chronic obstructive pulmonary disease (COPD) clinical trials aimed at evaluating treatment effects on exacerbations often suffer from early discontinuations of randomized treatment. Treatment discontinuations imply a loss of information and should ideally be considered in the statistical analysis of trial results, particularly if the discontinuations are related to the disease or treatment itself. Here, we explore this issue by investigating (1) whether there exists an association between the risks of exacerbation and treatment discontinuation in COPD clinical trials and (2) whether disregarding this association can cause bias in exacerbation treatment effect estimates. We focus on the hypothetical estimand, i.e. the treatment effect that would have been observed had all subjects completed the trial as planned. Methods The association between exacerbation and discontinuation risks was analysed by applying a joint frailty (random effect) model – allowing for the simultaneous analysis of multiple types of correlated events – to data from five Phase III-IV COPD clinical trials. Specifically, the impact of the association on exacerbation treatment effect estimates was assessed by comparing the treatment hazard ratios of the joint frailty model to the rate/hazard ratios of two related statistical models (the negative binomial and shared frailty models), which both assume discontinuations to be unrelated to the trial outcome. The models were also compared using simulated data. Results A statistically significant (p 5 percentage point difference in hazard/rate ratio). For some treatment comparisons in the clinical trials, the difference in treatment effect estimates between the joint frailty and the other models was as high as 10–15 percentage points. The difference was affected by the strength of the exacerbation-discontinuation association, the population heterogeneity in exacerbation risk, and the difference in discontinuation rates between treatment arms. Conclusions We have identified an association between the risks of exacerbation and treatment discontinuation in five COPD clinical trials. We recommend using the joint frailty model to account for this association when estimating exacerbation treatment effects, particularly when targeting the hypothetical estimand.

Abstract In this paper, we present algorithms that learn and update temporal node embeddings on the fly for tracking and measuring node similarity over time in graph streams. Recently, several representation learning methods have been proposed that are capable of embedding nodes in a vector space in a way that captures the network structure. Most of the known techniques extract embeddings from static graph snapshots. By contrast, modeling the dynamics of the nodes in temporal networks requires evolving node representations. In order to update node representations that reflect the temporal changes in the local graph structure, we rely on ideas for data stream algorithms. For example, we assess neighborhood overlap by a MinHash fingerprint-based algorithm. To evaluate our methods, in addition to the standard link prediction task, we provide dynamic ground truth data for the quantitative evaluation of similarity search by using online updated node embeddings. In our experiments, we constructed tennis tournament Twitter mention graphs as edge streams and compiled dynamic ground truth by using tournament schedule as external source. Our new algorithms outperformed snapshot-based batch methods for both link prediction and similarity search.

School refusal (SR) can have several negative consequences, but effective treatments are available. When chronic, school absence requires comprehensive treatment. This study evaluates an intervention for SR based on a Cognitive Behavioral Therapy (CBT) model, Hemmasittarprogrammet (HSP). Attendance, anxiety, depression, quality of life, and emotional and behavioral symptoms were measured at pre-treatment, post-treatment, and follow-up. The participants (n = 84; 69% male) were SR students between 10 and 17 years old and their parents. School attendance increased after treatment and at follow-up. The proportion of students totally absent from school decreased and the number of students with an acceptable level of school attendance increased. Levels of anxiety and depression were lower both post-treatment and at follow-up for the youths and their parents. HSP, a promising treatment program for school refusal, builds on the literature of CBT-based programs, which has been shown to be effective for SR treatment. However, more research about the effectiveness of the program is needed. Future studies should have a stronger research design, include a measure of fidelity, and be evaluated independent of the founders of the program under investigation.

Abstract A plethora of centrality measures or rankings have been proposed to account for the importance of the nodes of a network. In the seminal study of Boldi and Vigna (2014), the comparative evaluation of centrality measures was termed a difficult, arduous task. In networks with fast dynamics, such as the Twitter mention or retweet graphs, predicting emerging centrality is even more challenging. Our main result is a new, temporal walk based dynamic centrality measure that models temporal information propagation by considering the order of edge creation. Dynamic centrality measures have already started to emerge in publications; however, their empirical evaluation is limited. One of our main contributions is creating a quantitative experiment to assess temporal centrality metrics. In this experiment, our new measure outperforms graph snapshot based static and other recently proposed dynamic centrality measures in assigning the highest time-aware centrality to the actually relevant nodes of the network. Additional experiments over different data sets show that our method perform well for detecting concept drift in the process that generates the graphs.

Abstract Background The patient-reported outcome measures (PROMs), patient-reported experience measure (PREMs) and Effectiveness Programme (PPEP) launched with the aim of supporting all National Health Service Wales (NHS Wales) organisations to collect PROMs and PREMs across a range of conditions. The aim is to collect generic and condition-specific PROMs and PREMs electronically from every secondary care patient in Wales to provide a measure that can be used to determine the clinical and cost-effectiveness of treatments and services. This study reports on the experience of the PPEP in developing an electronic platform suitable for large-scale data collection, storage, analysis and reporting and identifies the problems encountered and solutions implemented using a generic PROM survey as an example. Methods The generic PROM survey is available in English and Welsh and consists of a consent section and three components: the EQ-5D-5L tool, the Work Productivity and Activity Impairment (WPAI) tool and a number of “about you” questions. The “about you” questions are designed to assess factors which may affect patient health and outcomes such as information on height, weight, smoking history, exercise levels and alcohol consumption. A dedicated PROM database was built, and links between the e-PROM platform and other key clinical databases within NHS Wales were developed. Results Pilot testing of the unvalidated sections of the generic electronic PROM found that most of the questions were well understood and easy to answer: however, feedback suggested some improvements and changes were required, specifically around questions relating to alcohol and exercise. Electronic PROM collection has been initiated in six of the seven health boards in Wales and at-home collection initiated in three health boards. More than 9300 patients have completed a PROM survey. Early results from one Health Board show that patients took approximately 10 min to complete the questionnaire with most patients answering an average of 94.7% of the questions. Conclusions Successful implementation of a PROM collection programme is dependent on a number of factors including close collaboration with clinicians, analysts, IT specialists and patients to ensure that any electronic system of PROM collection is fit for purpose and user friendly both for patients and clinicians.