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Abstract Microbubbles (MB) are widely used as contrast agents for ultrasound (US) imaging and US‐enhanced drug delivery. Polymeric MB are highly suitable for these applications because of their acoustic responsiveness, high drug loading capability, and ease of surface functionalization. While many studies have focused on using polymeric MB for diagnostic and therapeutic purposes, relatively little attention has thus far been paid to improving their inherent imaging and drug delivery features. This study here shows that manipulating the polymer chemistry of poly(butyl cyanoacrylate) (PBCA) MB via temporarily mixing the monomer with the monomer‐mimetic butyl cyanoacetate (BCC) during the polymerization process improves the drug loading capacity of PBCA MB by more than twofold, and the in vitro and in vivo acoustic responses of PBCA MB by more than tenfold. Computer simulations and physisorption experiments show that BCC manipulates the growth of PBCA polymer chains and creates nanocavities in the MB shell, endowing PBCA MB with greater drug entrapment capability and stronger acoustic properties. Notably, because BCC can be readily and completely removed during MB purification, the resulting formulation does not include any residual reagent beyond the ones already present in current PBCA‐based MB products, facilitating the potential translation of next‐generation PBCA MB.

Stable isotope analysis of plant remains recovered from archaeological sites is becoming more routine. There remains a lack of consensus, however, on how to appropriately select archaeological plant remains for isotopic analysis, how to account for differences in preservation and the effect of potential contamination, and how to interpret the measured isotope values in terms of the conditions in which the plants grew. In this paper, we outline the main issues to be considered when planning and conducting an isotopic study of archaeobotanical remains. These include: (1) setting out the research question(s) that will be answerable using available analytical approaches, (2) considering the archaeological context from which plant remains derive, (3) determining appropriate sample size through consideration of estimate precision, (4) establishing the conditions in which plant remains have been preserved and potential effects on their isotope values, and (5) accounting for possible contamination during deposition. With these issues in mind, we propose some recommendations for researchers to consider when planning and conducting an isotopic study of archaeobotanical remains.

We report anthropogenic particles (AP) > 100μm, including microplastics and microfibers, from 70 surface snow samples collected from the urban Greater Toronto Area (GTA), remote and sparsely inhabited regions in the Yukon and Northwest Territories, and the unpopulated high Arctic. Concentrations and proportions of particles of anthropogenic origin were conservatively estimated after blank and ‘anthropogenic origin’ corrections were performed based on visual analysis and micro-Fourier transform infrared spectroscopy (µFTIR). AP were dominated by microfibers (95-100%), with variable concentrations across and within regions. Microfibers were distinguished as synthetic, regenerated semi-synthetic, anthropogenically modified cellulosic, and natural cellulosic or proteinaceous. Among microfibers with confirmed anthropogenic origin, most were polyester/PET (8-22%) and semi-synthetic rayon (1-18%), with anthropogenic cellulose comprising a small proportion (3-7%) across all regional areas. Greater diversity of coloured non-fibrous particles (fragments, films and foams) in settled regions (i.e., GTA and Carcross, Yukon) suggests direct input from local sources. Back trajectory analyses performed for days leading up to sample collection showed high frequency transport (>10%) from population centres exceeding 200km distance. Our findings of APs in snow from uninhabited areas support the hypothesis that APs, especially microfibers, undergo long-range atmospheric transport whereby snow can scavenge and deposit APs in remote northern regions.

Background: Avocado intake has been associated with improvements in diet quality. Whether this response is because of avocado intake, per se, or combined with a food and/or nutrient displacement (D) has yet to be determined. Objectives: This secondary analysis, conducted using dietary data from the Habitual Diet and Avocado Trial, sought to assess the effect of consuming a large avocado (168 g, 281 kcal) daily in the avocado-supplemented diet (AD) group compared with the habitual diet (HD) group on food and nutrient D. Methods: Using data from 3 unannounced telephone 24-h dietary recalls conducted during the 6-mo intervention period, food intake data were evaluated for 898 participants, aged 25–87 y, and a BMI range of 20.5–60.3 kg/m2. The food group distribution, energy, and nutrient intake of the AD group (n = 436) were calculated and compared with those of the HD group (n = 462). Results: The AD group had a higher daily intake of energy (159 ± 575 kcal) (P < 0.001), potassium (3193 ± 817 mg compared with 2419 ± 843 mg) (P < 0.005), fiber (30 ± 8 g compared with 19 ± 9 g) (P < 0.05), and a lower daily intake of animal protein (49 ± 33 g compared with 55 ± 24 g) (P = 0.02) compared with the HD group. Partial D with an avocado was observed for energy (43%), total fat (23%), and carbohydrate (87%), indicating a lower intake of these nutrients from non-avocado sources in the AD group. Food group analysis revealed a lower consumption of animal-derived protein from red meat, processed meats, poultry, and fish in the AD group, with no significant differences observed in dairy and egg intake between groups. Conclusions: Incorporating 1 avocado daily led to favorable modifications in the dietary composition of participants, including an increase in potassium and fiber intake, which can improve diet quality.This trial was registered at https://clinicaltrials.gov as NCT03528031.

BackgroundSeveral studies have demonstrated an association between tricuspid regurgitation (TR) and organ dysfunction including hepatic and renal insufficiency. Improvement of liver function following transcatheter edge-to-edge repair (T-TEER) has already been linked to reduction of venous congestion due to TR reduction. This study analyzes whether TR-reduction using T-TEER is also associated with improved renal function.Methods and resultsThe TRIC-ULM registry includes 92 selected patients undergoing T-TEER between March 2017 and May 2023. Estimated glomerular filtration rate (eGFR) improvement was evident in 53 patients (57%) at 3-months follow-up (FU) and defined by FU eGFR > baseline eGFR. Median age was 80 [interquartile range 75–83] years, pre- and postinterventional TR grades were 4 [3–5] and 1 [1–2], baseline eGFR was 36 [30–53] ml/min and New Yeark Heart Association (NYHA) IV was evident in 15% of patients. Multiple logistic regression analysis revealed TR vena contracta reduction (Odds ratio (OR) 1.35 [95% CI: 1.12–1.64] per mm, p = 0.002) and reduced preinterventional tricuspid annular plane systolic excursion (TAPSE) [OR 0.89 (95% CI: 0.79–0.99) per mm, p = 0.033] to independently predict renal improvement at FU. An eGFR improvement threshold of >9 ml/min was associated with reduced 1-year heart failure hospitalization rates [adjusted hazard ratio 0.22 (95% CI: 0.07–0.62) p = 0.005].ConclusionEffective tricuspid edge-to-edge repair is associated with improved renal function and reduced heart failure hospitalization. In patients without renal improvement at 3-months follow-up, residual tricuspid regurgitation should be reevaluated for reintervention.

Background Optimal duration and choice of antiplatelet therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention remain controversial. Methods and Results Digital databases (PubMed, Cochrane, and Embase) were queried to select all randomized controlled trials on a post–percutaneous coronary intervention population with acute coronary syndrome. Dual‐antiplatelet therapy (DAPT) with aspirin and clopidogrel for 12 months was compared with 4 major strategies: high‐potency, high‐ to low‐potency, low‐dose, and short‐duration DAPT. A network meta‐analysis was performed to compare the safety and efficacy of different antiplatelet strategies. This study was the second updated manuscript under the International Prospective Register of Systematic Review registration (CRD42021286552). Thirty‐two randomized controlled trials comprising 103 459 (51 750 experimental, 51 709 control) patients were included. Compared with DAPT with aspirin and clopidogrel for 12 months, high‐ to low‐potency DAPT (risk ratio [RR], 0.69 [95% CI, 0.52–0.92]) and aspirin+prasugrel containing DAPT for 12 months (RR, 0.84 [95% CI, 0.72–0.98]) had a significantly lower, whereas DAPT for 1 month followed by clopidogrel only (RR, 1.59 [95% CI, 1.06–2.39]) had a higher, incidence of major adverse cardiovascular events at 1 year (median follow‐up). Prasugrel (RR, 1.35 [95% CI, 1.09–1.66]) and ticagrelor (RR, 1.38 [95% CI, 1.17–1.62]) containing DAPT for 12 months had significantly higher rates, whereas high‐ to low‐potency DAPT (RR, 0.85 [95% CI, 0.63–1.15]) had no significant risk of major bleeding. Conclusions Aspirin and ticagrelor for 3 months, followed by aspirin and clopidogrel for the remaining duration, can be considered the optimal strategy for treating post–percutaneous coronary intervention patients with acute coronary syndrome because of a significantly reduced risk of major adverse cardiovascular events without increasing the risk of bleeding.

BackgroundIn the United States, colorectal cancer (CRC) is the third leading cause of cancer death among Black men. Compared to men of all other races or ethnicities, Black men have the lowest rates of CRC screening participation, which contributes to later-stage diagnoses and greater mortality. Despite CRC screening being a critical component of early detection and increased survival, few interventions have been tailored for Black men. ObjectiveThis study aims to report on the multistep process used to translate formative research including prior experiences implementing a national CRC education program, community advisory, and preliminary survey results into a culturally tailored mobile health (mHealth) intervention. MethodsA theoretically and empirically informed translational science public health intervention was developed using the Behavioral Design Thinking approach. Data to inform how content should be tailored were collected from the empirical literature and a community advisory board of Black men (n=7) and reinforced by the preliminary results of 98 survey respondents. ResultsA community advisory board identified changes for delivery that were private, self-paced, and easily accessible and content that addressed medical mistrust, access delays for referrals and appointments, lack of local information, misinformation, and the role of families. Empirical literature and survey results identified the need for local health clinic involvement as critical to screening uptake, leading to a partnership with local Federally Qualified Health Centers to connect participants directly to clinical care. Men surveyed (n=98) who live or work in the study area were an average of 59 (SD 7.9) years old and held high levels of mistrust of health care institutions. In the last 12 months, 25% (24/98) of them did not see a doctor and 16.3% (16/98) of them did not have a regular doctor. Regarding CRC, 27% (26/98) and 38% (37/98) of them had never had a colonoscopy or blood stool test, respectively. ConclusionsWorking with a third-party developer, a prototype mHealth app that is downloadable, optimized for iPhone and Android users, and uses familiar sharing, video, and text messaging modalities was created. Guided by our results, we created 4 short videos (1:30-2 min) including a survivor vignette, animated videos about CRC and the type of screening tests, and a message from a community clinic partner. Men also receive tailored feedback and direct navigation to local Federally Qualified Health Center partners including via school-based family clinics. These content and delivery elements of the mHealth intervention were the direct result of the multipronged, theoretically informed approach to translate an existing but generalized CRC knowledge–based intervention into a digital, self-paced, tailored intervention with links to local community clinics. Trial RegistrationClinicalTrials.gov NCT05980182; https://clinicaltrials.gov/study/NCT05980182

Producing and maintaining sexually selected ornaments often hinders survival. Because viability-related traits dictate the survival costs conferred by sexual ornaments, the evolution of viability-related traits can limit and/or compensate for ornament evolution. Here, we examine how the ornamental coloration of male dragonflies co-adapts with thermal physiology—a key suite of viability-related traits that influences nearly all reproductive and ecological interactions. Males of many dragonfly species produce dark color patches on their wings to attract potential mates and intimidate reproductive rivals. However, dark coloration also subjects male dragonflies to heat stress in warm climates by absorbing excess solar radiation. Our phylogenetic comparative analyses revealed that dragonfly species with dark sexual coloration have also evolved increased critical thermal maxima, which may allow them to compensate for ornament-induced heating. This pattern of correlated evolution was especially strong for species that inhabit tropical climates, where the heating costs of dark coloration are most severe. Given that darkened sexual coloration is taxonomically widespread and consistently elevates body temperatures, the pattern of co-adaptation between sexual ornaments and thermal physiology found here could represent a key process driving eco-physiological divergence in the past and influencing how populations respond to the changing climates of the future.

IntroductionIn this paper we propose that one of the core developmental aims of adolescence is to cultivate a capacity for active balancing as the primary process for creating a coherent, agentic self capable of contributing to the functioning and purposes of the communities which adolescents inhabit, including society as a broader community. While there many valuable initiatives and programs to promote positive development, learning, and wellbeing, these efforts typically take a siloed approach focusing on one dimension of development (e.g., social-emotional learning), leaving adolescents to create coherence from these disconnected approaches. As adolescence face an increasingly uncertain future (e.g., career instability), serious threats to human survival (e.g., environmental degradation), social divides (e.g., political and ideological polarization), etc., a siloed approach to adolescent development is not simply outmoded but it reinforces a fragmented self.Conceptual model and backgroundIn this paper we argue that a siloed approach to adolescent development and learning may contribute to a fragmented sense of self and agency, which can be associated with increased vulnerability to mental health challenges. We first link the proposed developmental aim of adolescence to neuroscience findings that identify three brain changes during adolescence that lay the groundwork for cultivating active balancing and provide an ontogenetic neurological push for adolescents to learn and manage how to engage their worlds. Leveraging this ontogenetic push, we propose adolescents can cultivate their capacity for active balancing within the cultural communities of practice they inhabit. These communities provide a ready and powerful fusion of action, affect, and thought into coherent and relevant understandings of the why, how, and utility of practices in a community, or what we label orientations. Active balancing is the process of actively seeking to establish or reestablish one's intended balance among these orientations.Conclusions and implicationsBuilding the capacity for active balancing, we suggest, engenders greater resilience and adaptability to a range of situations, a tolerance for and ability to resolve tensions, and an ability to transcend vast differences, including cultural and ideological. Implications for both the adolescent and society are discussed.

Laser powder bed fusion (L-PBF) enables direct manufacturing of components with complex geometries and thin walls, but many authors report size-dependent mechanical properties that may complicate design. Size effects are commonly attributed to surface roughness, microstructure, and/or internal defects, but the relative importance of each is still not fully understood. To systematically study these effects, L-PBF specimens made of two microstructurally-distinct stainless steels (17-4PH and 316L) were manufactured and mechanically tested, in varied heat-treatment conditions and across a range of thicknesses and build angles. It was found that the size-dependent mechanical properties are efficiently predicted by the ratio of surface roughness to specimen thickness, Ra/t, in a way that is relatively microstructure-agnostic. This metric is particularly useful for predicting ultimate strength and elongation, while microstructure moderates its predictive power for yield strength, especially in the more processing-sensitive 17-4PH. When considered in isolation, thickness or surface roughness had weaker correlations with mechanical properties and, importantly, tended to correlate much more strongly with one steel's properties than the other's. Comparing this comprehensive dataset with summary data from other researchers highlights the utility of Ra/t, and provides semi-quantitative estimates of the relative impacts of porosity, microstructure, and Ra/t on size-dependent properties.

The bone-resorbing activity of osteoclasts plays a critical role in the life-long remodeling of our bones that is perturbed in many bone loss diseases. Multinucleated osteoclasts are formed by the fusion of precursor cells, and larger cells – generated by an increased number of cell fusion events – have higher resorptive activity. We find that osteoclast fusion and bone resorption are promoted by reactive oxygen species (ROS) signaling and by an unconventional low molecular weight species of La protein, located at the osteoclast surface. Here, we develop the hypothesis that La’s unique regulatory role in osteoclast multinucleation and function is controlled by an ROS switch in La trafficking. Using antibodies that recognize reduced or oxidized species of La, we find that differentiating osteoclasts enrich an oxidized species of La at the cell surface, which is distinct from the reduced La species conventionally localized within cell nuclei. ROS signaling triggers the shift from reduced to oxidized La species, its dephosphorylation and delivery to the surface of osteoclasts, where La promotes multinucleation and resorptive activity. Moreover, intracellular ROS signaling in differentiating osteoclasts oxidizes critical cysteine residues in the C-terminal half of La, producing this unconventional La species that promotes osteoclast fusion. Our findings suggest that redox signaling induces changes in the location and function of La and may represent a promising target for novel skeletal therapies.

Introduction Hepatocellular carcinoma (HCC) is the fastest-rising and fourth most common cause of cancer death worldwide. Liver cirrhosis is the largest underlying risk factor for HCC. Therefore, patients with cirrhosis should have regular ultrasound and biochemical screening to pick up early HCC. Early HCC can be cured; more advanced HCCs have limited treatment options and poor prognosis. Current screening methods are suboptimal with poor sensitivity in picking up early disease. In this study, the investigators aim to recruit people with liver cirrhosis into a Prospective cohort for early detection of liver cancer—the Pearl cohort. The investigators believe that by using state-of-the-art tests we can improve the detection of early HCC.Methods and analysis This is a UK-based prospective, longitudinal, diagnostic, prognostic, multicentre, non-CTIMP study. Aiming to recruit 3000 patients with liver cirrhosis without a HCC diagnosis, the Pearl cohort will be followed actively for 3 years from recruitment and then passively via registry data for ten years thereafter. Blood and urine samples will be taken and information from routine care will be gathered. These will be used to assess novel diagnostic approaches for the detection early HCC and to develop models to identify those most at risk for developing HCC.Participants will be linked to national UK health registries to ensure long-term capture of HCC incidence and other relevant endpoints. Approximately 75 patients are predicted to develop de novo HCC within the 3-year follow up period. After this period, the study teams will obtain data on participants for at least 10 years after the last contact. This cohort will help develop an understanding of the incidence of HCC in a UK population stratified by underlying cirrhosis aetiology.Ethics and dissemination Ethical approval has been granted by REC and the trial is registered on ClinicalTrials.gov. The results will be published in peer-reviewed journals and presented at relevant meetings.Trial registration number NCT05541601.

Lithium-ion batteries have been rapidly developed as clean energy sources in many industrial fields, such as new energy vehicles and energy storage. The core issues hindering their further promotion and application are reliability and safety. A digital twin model that maps onto the physical entity of the battery with high simulation accuracy helps to monitor internal states and improve battery safety. This work focuses on developing a digital twin model via a mechanism-data-driven parameter updating algorithm to increase the simulation accuracy of the internal and external characteristics of the full-time domain battery under complex working conditions. An electrochemical model is first developed with the consideration of how electrode particle size impacts battery characteristics. By adding the descriptions of temperature distribution and particle-level stress, a multi-particle size electrochemical-thermal-mechanical coupling model is established. Then, considering the different electrical and thermal effect among individual cells, a model for the battery pack is constructed. A digital twin model construction method is finally developed and verified with battery operating data.

Background: Perioperative complications of deep vein thrombosis are well described in the total joint arthroplasty (TJA) literature. Few studies have investigated short-term perioperative outcomes of patients with primary hypercoagulable diseases (PHDs). Optimal perioperative management of PHD patients remains unknown, and they are often referred to tertiary centers for care. We investigated the influence perioperative hematology consultation and anti-coagulation use had on PHD patient outcomes following TJA surgery within the 90-day postoperative period. Methods: This retrospective cohort study examined perioperative outcomes of PHD patients undergoing TJA. Thirty-eight PHD patients were identified and compared to a 3:1 matched control group in a consecutive series of 6568 cases (2007-2019). Perioperative hematology consultations, use of anticoagulants (AC) or antiplatelet therapy, emergency department (ED) visits, readmissions, and complications within 90 days of surgery were determined. Results: The PHD cohort exhibited more frequent hematology consultations (odds ratio 5.88, 95% confidence interval: 2.59-16.63) and AC use (odds ratio 7.9, 95% confidence interval: 3.38-23.80) than controls. PHD patients did not show significantly greater rates of deep vein thrombosis, transfusion, infection, ED visits, or need for operative intervention. Similarly, AC vs antiplatelet therapy yielded comparable ED visits and readmissions within 90 days postoperatively (11.0% vs 9.7%, P = .85 and 5.5% vs 5.5%, P = 1, respectively). Conclusions: These findings suggest that despite increased hematology consultation and AC use, PHD patients do not demonstrate significantly elevated perioperative risks post-TJA, favoring careful preoperative workup and outpatient postoperative follow-up.

A long-standing question concerns whether sensory input can reach semantic stages of processing in the absence of attention and awareness. Here, we examine whether the N400, an event related potential associated with semantic processing, can occur under conditions of inattentional blindness. By employing a novel three-phase inattentional blindness paradigm designed to maximise the opportunity for detecting an N400, we found no evidence for it when participants were inattentionally blind to the eliciting stimuli (related and unrelated word pairs). In contrast, participants noticed the same task-irrelevant word pairs when minimal attention was allocated to them, and a small N400 became evident. When the same stimuli were fully attended and relevant to the task, a robust N400 was observed. In addition to univariate ERP measures, multivariate decoding analyses were unable to classify related from unrelated word pairs when observers were inattentionally blind to the words, with decoding reaching above-chance levels only when the words were (at least minimally) attended. By comparison, decoding reached above-chance levels when contrasting word pairs with non-word stimuli, even when participants were inattentionally blind to these stimuli. Our results also replicated several previous studies by finding a “visual awareness negativity” (VAN) that distinguished task-irrelevant stimuli that participants noticed compared with those that were not perceived, and a P3b (or “late positivity”) that was evident only when the stimuli were task relevant. Together, our findings suggest that semantic processing might require at least a minimal amount of attention.

The monitoring of plant diseases in nurseries, breeding farms and orchards is essential for maintaining plant health. Fire blight (Erwinia amylovora) is still one of the most dangerous diseases in fruit production, as it can spread epidemically and cause enormous economic damage. All measures are therefore aimed at preventing the spread of the pathogen in the orchard and containing an infection at an early stage [1–6]. Efficiency in plant disease control benefits from the development of a digital monitoring system if the spatial and temporal resolution of disease monitoring in orchards can be increased [7]. In this context, a digital disease monitoring system for fire blight based on RGB images was developed for orchards.Between 2021 and 2024, data was collected on nine dates under different weather conditions and with different cameras. The data source locations in Germany were the experimental orchard of the Julius Kühn Institute (JKI), Institute of Plant Protection in Fruit Crops and Viticulture in Dossenheim, the experimental greenhouse of the Julius Kühn Institute for Resistance Research and Stress Tolerance in Quedlinburg and the experimental orchard of the JKI for Breeding Research on Fruit Crops located in Dresden–Pillnitz. The RGB images were taken on different apple genotypes after artificial inoculation with Erwinia amylovora, including cultivars, wild species and progeny from breeding.The presented ERWIAM dataset contains manually labelled RGB images with a size of 1280 × 1280 pixels of fire blight infected shoots, flowers and leaves in different stages of development as well as background images without symptoms. In addition, symptoms of other plant diseases were acquired and integrated into the ERWIAM dataset as a separate class. Each fire blight symptom was annotated with the Computer Vision Annotation Tool (CVAT [8]) using 2-point annotations (bounding boxes) and presented in YOLO 1.1 format (.txt files). The dataset contains a total of 1611 annotated images and 87 background images. This dataset can be used as a resource for researchers and developers working on digital systems for plant disease monitoring.

The United Network for Organ Sharing (UNOS) heart transplant allocation policy was changed in 2018. This study examines the impact of the change in UNOS heart transplant allocation policy on the use of temporary mechanical circulatory support (MCS) devices and post-transplant survival.The analysis included a total of 26,481 patients listed and transplanted between January 2013 and June 2022. The results showed a decrease in waiting time for transplant after the policy change, indicating a successful reduction in waitlist time for high-priority status patients. However, the length of hospital stays from transplant to discharge increased following the policy change. The study also found an increase in the frequency of ECMO and IABP use both at the time of listing and at the time of transplant following the policy change.Cumulative patient and graft survival at 1000 days decreased following the policy change (86.1 per cent versus 83.7 per cent at 1000 days, p = 0.002). However, the survival curves showed similar survival trends in the first 2 years, with late divergence in survival occurring after 2 years.In conclusion the latest UNOS heart transplant allocation policy change led to a decrease in waiting times and an increase in the use of temporary MCS devices. There was a decrease in cummulative survival at 1000 days following the policy change.

The present study aims to describe the chair, bed, and toilet heights in rehabilitation hospitals and home environments to challenge rehabilitation clinicians to better prepare stroke survivors for discharge home. This study uses analysis of secondary outcomes from a multicentre, phase II randomized controlled trial (HOME Rehab trial) and additional observation of hospital environment. Data were collected from six rehabilitation hospitals and the homes of two hundred first-time stroke survivors who were aged >45 years. Chair, bed and toilet heights were measured; we measured 936 chairs and beds in hospital (17%) and home (83%) environments. Mean chair height at home was 47 cm (SD 6), which was 2 cm (95% CI, 0-4) lower than in the hospital ward and 5 cm (95% CI, 3-7) lower than in the hospital gym. Mean toilet height at home was 42 cm (SD 3), which was 3 cm (95% CI, 2-4) lower than in the hospital. Study findings suggest a disparity in heights between hospitals and home. Although clinicians may be aware of this disparity, they need to ensure that chair and bed heights within the hospital environment are progressively made lower to better prepare stroke survivors for discharge home.

BACKGROUND: Recent trends in Switzerland indicate a concerning rise in simultaneous polysubstance use among adolescents, a practice marked by the concurrent or sequential consumption of multiple psychoactive substances, notably alcohol and cannabis, alongside prescription medications (e.g. benzodiazepines) and illicit drugs, resulting in dozens of fatal outcomes. However, data on simultaneous polysubstance use and evidence-based approaches to effective prevention is lacking. AIMS OF THE STUDY: The study aimed to explore and gain insights into use patterns, use settings, use motives, harm-reduction strategies, concerns associated with substance use, and support and counselling services from the point of view of adolescents practicing simultaneous polysubstance use in Switzerland. METHODS: An exploratory study was conducted via an online survey (n = 116) and two focus group discussions with affected Swiss adolescents aged 14 to 20. A mixed-methods approach was applied to gain insights and better understand the phenomenon of simultaneous polysubstance use among Swiss adolescents. Quantitative survey data obtained between November 2021 and March 2023 by means of convenience sampling – organised by distributing flyers (in three national languages) among several project partners, on the internet, over social media and by word of mouth – was analysed descriptively, whereas qualitative survey data and focus group data were thematically explored. A concurrent nested design was employed, utilising quantitative findings as a core foundation for addressing research questions, while qualitative findings were instrumental in validating and providing contextual depth to the results. RESULTS: Our findings reveal a preference of the sample for combining alcohol with cannabis and/or other substances (e.g. benzodiazepines or hard drugs) in social settings, driven by diverse motives, including enhancement of experiences and partly maladaptive coping mechanisms leading to self-medication. Despite some awareness of the potential harms, there is a significant reliance on peer-shared strategies for harm reduction, highlighting a gap in formal support and counselling services, some of which are perceived by adolescents as lacking empathy and relevance. CONCLUSIONS: This study underscores the urgency of developing targeted, youth-centred interventions that resonate with the lived realities of adolescents, aiming not only to reduce substance use but also to address the broader psychosocial factors contributing to simultaneous polysubstance use. By shedding light on the complex dynamics of adolescent polysubstance use, our research contributes to the ongoing dialogue on effective prevention strategies, advocating for a holistic approach encompassing education, policy reform and community support to tackle this multifaceted public health challenge.

Background: The syndemic of HIV, substance use (SU), and mental illness has serious implications for HIV disease progression among women. We described co-utilization of HIV care, SU treatment, and mental health treatment among women with or at risk for HIV. Methods: We included data from women with or at risk for HIV (n = 2559) enrolled in all 10 sites of the Women’s Interagency HIV Study (WIHS) from 2013 to 2020. Current SU was defined as self-reported, non-medical use of drugs in the past year, excluding use of only marijuana. Tobacco and alcohol were assessed separately. We described co-utilization of SU treatment, tobacco and alcohol use treatment, HIV care, and mental health care in the past year among women who were eligible for each service. We compared service utilization by those who did/did not utilize SU treatment using Wald Chi-square tests. Results: Among women with current SU (n = 358), 42% reported utilizing SU treatment. Among those with current SU+HIV (n = 224), 84% saw their HIV provider, and 34% saw a mental health provider. Among women with current SU+heavy alcohol use (n = 95), 18% utilized alcohol use treatment; among current SU+tobacco use (n = 276), 8% utilized tobacco use treatment. Women who utilized SU treatment had higher utilization of alcohol use treatment (59% vs. 5%; P

Abstract Background Facet fractures are frequently associated with clinically observed cervical facet dislocations (CFDs); however, to date there has only been one experimental study, using functional spinal units (FSUs), which has systematically produced CFD with concomitant facet fracture. The role of axial compression and distraction on the mechanical response of the cervical facets under intervertebral motions associated with CFD in FSUs has previously been shown. The same has not been demonstrated in multi‐segment lower cervical spine specimens under flexion loading (postulated to be the local injury vector associated with CFD). Methods This study investigated the mechanical response of the bilateral inferior C6 facets of thirteen C5‐C7 specimens (67±13 yr, 6 male) during non‐destructive constrained flexion, superimposed with each of five axial conditions: (1) 50 N compression (simulating weight of the head); (2‐4) 300, 500, and 1000 N compression (simulating the spectrum of intervertebral compression resulting from neck muscle bracing prior to head‐first impact and/or externally applied compressive forces); and, (5) 2 mm of C6/C7 distraction (simulating the intervertebral distraction present during inertial loading of the cervical spine by the weight of the head). Linear mixed‐effects models (α = 0.05) assessed the effect of axial condition. Results Increasing amounts of intervertebral compression superimposed on flexion rotations, resulted in increased facet surface strains (range of estimated mean difference relative to Neutral: maximum principal = 77 to 110 με, minimum principal = 126 to 293 με, maximum shear = 203 to 375 με) and angular deflection of the bilateral inferior C6 facets relative to the C6 vertebral body (range of estimated mean difference relative to Neutral = 0.59° to 1.47°). Conclusions These findings suggest increased facet engagement and higher load transfer through the facet joint, and potentially a higher likelihood of facet fracture under the compressed axial conditions.

CRISPR/Cas9 genome editing is a rapidly advancing technology that has the potential to accelerate research and development in a variety of fields. However, manual genome editing processes suffer from limitations in scalability, efficiency, and standardization. The implementation of automated systems for genome editing addresses these challenges, allowing researchers to cover the increasing need and perform large-scale studies for disease modeling, drug development, and personalized medicine. In this study, we developed an automated CRISPR/Cas9-based genome editing process on the StemCellFactory platform. We implemented a 4D-Nucleofector with a 96-well shuttle device into the StemCellFactory, optimized several parameters for single cell culturing and established an automated workflow for CRISPR/Cas9-based genome editing. When validated with a variety of genetic backgrounds and target genes, the automated workflow showed genome editing efficiencies similar to manual methods, with indel rates of up to 98%. Monoclonal colony growth was achieved and monitored using the StemCellFactory-integrated CellCelector, which allowed the exclusion of colonies derived from multiple cells or growing too close to neighbouring colonies. In summary, we demonstrate the successful establishment of an automated CRISPR/Cas9-based genome editing process on the StemCellFactory platform. The development of such a standardized and scalable automated CRISPR/Cas9 system represents an exciting new tool in genome editing, enhancing our ability to address a wide range of scientific questions in disease modeling, drug development and personalized medicine.

Background Direct oral anticoagulants (DOACs) have complex dosing regimens and are often incorrectly prescribed. We evaluated a nationwide DOAC population management dashboard rollout whose purpose includes pharmacist review and correction of off‐label dosing prescriptions. Methods and Results Using data from Veterans Health Affairs, we identified all patients prescribed DOACs for atrial fibrillation or venous thromboembolism between August 2015 and December 2019. Sites were grouped on the basis of the timing of moderate‐high usage of the DOAC population management tool dashboard. Effectiveness was defined as the monthly rate of off‐label DOAC prescribing and the rate of clinical adverse events (bleeding, composite of stroke or venous thromboembolism). Implementation was evaluated as the percentage of off‐label DOAC prescriptions changed within 7 days. Among the 128 652 patients receiving DOAC therapy at 123 centers, between 6.9% and 8.6% had off‐label DOAC prescriptions. Adoption of the DOAC population management tool dashboard before July 2018 was associated with a decline in off‐label dosing prescriptions (8.7%–7.6%). Only 1 group demonstrated a significant reduction in monthly rates of bleeding following implementation. All sites experienced a reduction in the composite of venous thromboembolism or stroke following dashboard adoption. There was no difference in the implementation outcome of DOAC prescription change within 7 days in any of the adoption groups. Conclusions Early adoption of the DOAC population management tool dashboard was associated with decreased rates of off‐label DOAC dosing prescription and reduced bleeding. Following adoption of the DOAC population management tool dashboard, all sites experienced reductions in venous thromboembolism and stroke events.

Effective treatment and immunoprophylaxis of viral respiratory infections with neutralizing monoclonal antibodies (mAbs) require maintaining inhibitory concentrations of mAbs at the airway surface. While engineered mAbs with increased affinity to the neonatal Fc receptor (FcRn) are increasingly employed, little is known how increased affinity of Fc to FcRn influences basal-to-apical transepithelial transport (transcytosis) of mAbs across the airway epithelium. To investigate this, we utilized a model of well-differentiated human airway epithelium (WD-HAE) that exhibited robust FcRn expression, and measured the transepithelial transport of a mAb against SARS-CoV-2 Spike protein (CR3022) with either wildtype IgG1-Fc or Fc modified with YTE or LS mutations known to increase affinity for FcRn. Despite the marked differences in the affinity of these CR3022 variants for FcRn, we did not find substantial differences in basal-to-apical transport reflective of systemic dosing, or apical-to-basal transport reflective of inhaled dosing, compared to the transport of wildtype IgG1-Fc. These results suggest increasing FcRn affinity may only have limited influence over transcytosis rates of systemically dosed mAbs across the human airway epithelium over short time scales. Over longer time scales, the elevated circulating levels of mAbs with greater FcRn affinity, due to more effective FcRn-mediated recycling, may better resupply mAb into the respiratory tract, leading to more effective extended immunoprophylaxis.

Abstract The motor impairments experienced by people with Parkinson's disease (PD) are exacerbated during memory‐guided movements. Despite this, the effect of antiparkinson medication on memory‐guided movements has not been elucidated. We evaluated the effect of antiparkinson medication on motor control during a memory‐guided reaching task with short and long retention delays in participants with PD and compared performance to age‐matched healthy control (HC) participants. Thirty‐two participants with PD completed the motor section of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS III) and performed a memory‐guided reaching task with two retention delays (0.5 s and 5 s) while on and off medication. Thirteen HC participants completed the MDS‐UPDRS III and performed the memory‐guided reaching task. In the task, medication increased movement velocity, decreased movement time, and decreased reaction time toward what was seen in the HC. However, movement amplitude and reaching error were unaffected by medication. Shorter retention delays increased movement velocity and amplitude, decreased movement time, and decreased error, but increased reaction times in the participants with PD and HC. Together, these results imply that antiparkinson medication is more effective at altering the neurophysiological mechanisms controlling movement velocity and reaction time compared with other aspects of movement control.

Objective/Approach The Black Health Equity Working Group's Applied Health Research Question aimed to compare cancer screening rates and surgical wait times between community health centre (CHC) clients based on race-related data and non-CHC clients. CHC client data was categorized by self-identified racial groups, with Black self-identification compared to non-Black racialized, White, and missing racial self-identification, and non-CHC clients. Health card numbers were encrypted to link individuals to the Primary Care Population dataset for breast, cervical, and colorectal cancer screening rates. Surgical wait time indicators, such as the number of patients undergoing surgery and average wait times for initial consultation and completed surgeries, were derived from the Wait Time Information System. Assessments were conducted semi-annually from fiscal year 2018 to 2021. Results Following the onset of COVID-19, CHC clients self-identifying as Black experienced the most significant decrease (6.8%) in colorectal screenings compared to other groups. Mammogram screenings remained consistently higher for CHC clients self-identifying as Black pre- and post-pandemic. Average cervical cancer screening rates were approximately 8% higher among CHC clients compared to non-CHC clients, irrespective of racial self-identification. However, due to small sample sizes and missing data among self-identified racial groups, trends in surgical wait times for both CHC and non-CHC clients were unstable. Conclusion/Implications Tailored interventions targeting Black CHC clients can enhance cancer screening rates, particularly colorectal screenings. The analysis of CHC data offers valuable insights into race-based disparities in health outcomes. Improved data completeness is essential for accurately assessing health outcome variations among different racial groups.

Objective To highlight progress in facilitating and supporting pan-Canadian data analysis research that is supported by a central coordinating center. This process will be illustrated with the use of a recently completed project that has been supported using data from Alberta, British Columbia, and Ontario. Approach The project represents a significant endeavor within the central coordinating center, as it necessitates coordination for data access, data importation and analytical support across three provinces. The focus will be on the administrative processes refined to support collaborative research endeavors. While specific project details will remain undisclosed, procedural enhancements within the central coordinating center framework will be highlighted. Key discussion points include standardized protocols for data access, collaborative efforts to streamline data importation, and facilitation of analytical support across jurisdictions. The type of cross-jurisdictional analytic support will as well be highlighted; data variables harmonization and sharing of data algorithms cohorts across the participating provincial data centers in support of the meta-analysis. Results The successful completion of the final data analysis underscores the effectiveness of a unified data access coordination center for researchers seeking multi-regional health data in Canada. By highlighting advancements enabled by the central coordinating center and provincial data centers, this submission aims to inform researchers about the current landscape of pan-Canadian research and foster opportunities for future collaboration. Implications Sharing insights and lessons from this project emphasizes the advancements facilitated by the central coordinating center and provincial data centers, informing researchers about the potential of pan-Canadian research, and encouraging future collaborative endeavors.

Objective Alberta's largest research universities collaborated to expand COVID-19 wastewater monitoring throughout the province to regularly provide evidence of SARS-CoV-2 burden in municipalities representing 3.2 million people. Approach Sampling was conducted at 26 wastewater treatment plants and facilities across the province. The project quantified SARS-CoV-2 genomic material in wastewater to reveal population-level trends of COVID-19 cases. This inclusive and comprehensive strategy captures everyone who contributes to wastewater, including those not clinically diagnosed. Researchers collected wastewater samples in municipalities three times a week. Additional sentinel monitoring was undertaken in neighbourhoods, hospitals, long-term care facilities, worksites, shelters, and schools. Results were shared on the public COVID Data Tracker website (https://covid-tracker.chi-csm.ca/). Data was additionally linked with hospital outcomes, workforce absenteeism and outbreak information. Results Wastewater-based surveillance (WBS) for SARS-CoV-2 genomic RNA associates very strongly with clinically diagnosed cases and health resource utilization, providing a ≥6-day leading indicator. WBS can effectively be performed across a range of geographic scales (from cities to individual facilities), ensuring actionable data that is relevant to end-users. We have published how outbreaks across a range of high-risk facilities can be monitored and predicted with WBS and can also be used to model COVID-19-associated workforce absenteeism. Emails and website interactions suggested widespread citizen engagement using data for evidence-based decisions. Conclusion WBS is a valuable tool for identifying potential outbreaks and tailoring response measures at the policy level and by individual citizens. We've created customizable real-time data-sharing tools catering to both the public (enhanced data transparency) and government (actionable insights).

Objective Amid a drug poisoning epidemic, UCalgary adapted its comprehensive wastewater monitoring program to track illicit drug use. The joint initiative between the academic community and Alberta municipalities aims to provide early warning information on changes in the drug supply to healthcare workers, policymakers, and people with substance use disorders (pwSUD). Approach The logistic network, first used for SARS-CoV-2 monitoring, has evolved to track 48 substances linked to substance use. These include the parent drugs (e.g., cocaine, methamphetamines, various opiates) and their metabolites. The comprehensive nature of this tracking provides a nuanced understanding of trends. Collected up to 3X-weekly across various locations in Alberta including municipal wastewater treatment plants, entire neighbourhoods, and shelters, the data reveals geographical and temporal patterns in substance use. Findings were cross validated with Alberta’s substance use surveillance system to predict trends in wastewater, correlating with emergency and inpatient admissions and overdose deaths. Results The research uncovered noteworthy trends. Intermittent, alarming, spikes in carfentanyl, benzodiazepines, and xylazine in wastewater were observed during periods of elevated Emergency Medical Services (EMS) responses to opioid-related incidents in the year 2023. This correlation underscores the real-world impact of the identified substance trends, emphasizing the urgency for targeted interventions to address the escalating opioid crisis. Further work to create a dashboard with additional data sources has begun. Conclusions Timely data on the dynamic drug supply is crucial in addressing the ongoing drug poisoning crisis. The team is exploring ways to share information with emergency responders, healthcare providers, government officials, and pwSUD.

ABSTRACT Objective: The aim of this study was to examine the association between bullying victimization and health risk behaviors in adolescents. Methods: A representative sample of 1020 adolescents participated in the study. The variables such as bullying, health risk behaviors (tobacco, drugs, alcohol, sedentary behavior, smartphone use, level of physical activity, and sleep), and economic status were assessed using self-reported questionnaires. Odds ratios with 95% confidence intervals (95%CI) were obtained using binary logistic regression and ordinal, gross, and adjusted logistic regression (p

ABSTRACT Objective: The aim of this study was to analyze the association between participation in fitness-related exercises (FRE) and body image dissatisfaction (BID) in adolescents and evaluate the interaction between physical exercise and nutritional status in this association. Methods: A cross-sectional study was conducted in 2015 involving 799 adolescents (10–16 years old) from 14 public schools in Curitiba (PR), Brazil. BID was assessed using the Body Shape Questionnaire and the Silhouette Scale. The FRE was classified as “does not practice,” “practices ≤300 min/week,” and “practices >300 min/week” by the Physical Activity Questionnaire for Adolescents. Poisson and multinomial logistic regressions, adjusted for sex, sexual maturation, and nutritional status analyzed the association of FRE and BID. Results: The BID prevalence was 28.3%; 52.4% of the adolescents wanted to reduce their silhouettes; and 48.7% did not practice FRE. Adolescents who practiced FRE >300 min/week had a 28% higher prevalence for some level of BID (PR 1.28; 95%CI 1.08–1.52) and a 46% lower chance of wanting to reduce silhouettes (OR 0.54; 95%CI 0.35–0.82), compared to nonpractitioners. There was no interaction between FRE and nutritional status in association with BID. Conclusions: The adolescents who practice FRE >300 min/week are likely to have some level of BID and are less likely to report the desire to increase their silhouettes, regardless of their nutritional status.

Abstract Riverbeds often fine downstream, with a gravel‐bedded reach, a relatively abrupt gravel‐sand transition (GST), and a sand‐bedded reach. Underlying this behavior, bed grain size distributions are often bimodal, with a relative paucity (gap) around the range 1–5 mm. There is no general morphodynamic model capable of producing the grain size gap and gravel‐sand transition autogenically from a unimodal sediment supply. Here we use a one‐dimensional morphodynamic model including size‐specific bedload and suspended load transport, to show that bimodality readily evolves autogenically even under unimodal sediment feed. A GST forms when we include a floodplain width that abruptly increases at some point. Upstream of the transition, non‐gap gravel ceases to move and gap sediment is preferentially transported. At the transition, non‐gap sand rapidly deposits from suspension, enhancing gap sediment mobility and diluting its presence on the bed.

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) following oral or intravenous chemotherapy often results in neuropathic pain, accompanied by symptoms such tingling, burning and hypersensitivity to stimuli, with a notable decline in quality of life (QoL). Effective therapies for CIPN are lacking, with a high demand for analgesics to address this issue. The QUCIP study aimed to assess the effectiveness of high concentration (179 mg) capsaicin patch (HCCP) in alleviating neuropathic pain and associated symptoms in breast cancer patients with confirmed CIPN.MethodsQUCIP is a prospective, multi-center observational study spanning 36 weeks with up to three HCCP treatments. Initial treatment (visit V0) was followed by two telephone contacts (T1, T2) and subsequent face-to-face visits every 12 weeks or upon retreatment (visits V1–V3). 73 female patients with painful CIPN post neoadjuvant/adjuvant breast cancer therapy were enrolled. Primary endpoint was the reduction of neuropathic pain symptom score (painDETECT®). Secondary endpoints included improvements in CIPN-specific QoL (QLQ-CIPN20), reductions in pain intensity (numeric pain rating scale, NPRS), and achievement of ≥ 30% and ≥ 50% pain reduction.ResultsMedian age was 61 years, with 52.0% of patients experiencing peripheral neuropathic pain for > 1 year (> 2 years: 34.2%). The painDETECT® score significantly decreased from baseline (19.71 ± 4.69) to 15.80 ± 6.20 after initial treatment (p < 0.0001) and continued to decrease at follow-up visits. The NPRS indicated significant pain intensity reduction at each time point, particularly pronounced in patients receiving three HCCP treatments. Clinically significant pain relief of ≥ 30% increased from 25.0% at week 4 (T2) to 36.2%, 43.5%, and 40.0% at weeks 12 (V1), 24 (V2), and 36 (V3), respectively. The percentage of patients achieving pain relief of ≥ 50% increased from 14.7% at T2 to 15.5%, 21.7% and 32.5% at V1, V2 and V3, respectively. Patients further reported a significant improvement in their CIPN-related QoL throughout the study. Adverse drug reactions (ADRs) mainly included application site reactions.ConclusionIn this study, HCCP shows benefit in managing CIPN in real-world settings. The data demonstrate a sustained and progressive reduction in neuropathic pain and symptomatology, confirming the clinical benefit of repeated treatment observed in former clinical trials. HCCP treatment has also the potential to significantly improve the QoL associated with CIPN. The safety profile of HCCP was confirmed, supporting its use in clinical practice.

The first measurement of two-particle angular correlations for charged particles with LEP-II data is presented. The study is performed using archived hadronic e+e− data collected by ALEPH at center-of-mass energies up to 209 GeV, above the W+W− production threshold, which provide access to unprecedented charged-particle multiplicities and more complex color-string configurations if compared to previous measurements at LEP-I energies. An intriguing long-range near-side excess is observed in the correlation function measured with respect to the thrust axis in the highest multiplicity interval (Ntrk≥50). Such a structure is not predicted by the Monte-Carlo simulation. The harmonic anisotropy coefficients vn, which result from the Fourier expansion of the two-particle correlation functions, were also measured for the first time in e+e− data, and compared to pythia 6 predictions and to the results obtained in proton-proton collisions. The results presented in the Letter provide novel experimental constraints on the formation of collective phenomena in point-like e+e− collisions.

Purpose/Objectives: Retrospective analysis suggests that dose escalation to a biologically effective dose of more than 70 Gy may improve overall survival in patients with pancreatic ductal adenocarcinoma (PDAC), but such treatments in practice are limited by proximity of organs at risk (OARs). We hypothesized that CT-guided online adaptive radiotherapy (OART) can account for interfraction movement of OARs and allow for safe delivery of ablative doses. Materials/Methods: This is a single institution retrospective analysis of patients with PDAC treated with OART on the Ethos platform (Varian Medical Systems, a Siemens Healthineers Company, Palo Alto). All patients were treated to 40 Gy in 5 fractions. PTV overlapping with a 5 mm planning risk volume expansion on the stomach, duodenum and bowel received 25 Gy. Initial treatment plans were created conventionally. For each fraction, PTV and OAR volumes were recontoured with AI assistance after initial cone beam CT (CBCT). The adapted plan was calculated, underwent QA, and then compared to the scheduled plan. A second CBCT was obtained prior to delivery of the selected plan. Total treatment time (first CBCT to end of radiation delivery) and active physician time (first to second CBCT) were recorded. PTV_4000 V95 %, PTV_2500 V9 5%, and D0.03 cc to stomach, duodenum and bowel were reported for scheduled (S) and adapted (A) plans. CTCAEv5.0 toxicities were recorded. Statistical analysis was performed using a two-sided T test and α of 0.05. Results: 21 patients with unresectable or locally-recurrent PDAC were analyzed, with a total of 105 fractions. Average total time was 29 min and 16 s (16:36–49:40) and average active physician time was 19:41 min (9:25–39:34). All fractions were treated with adapted plans. 97 % of adapted plans met PTV_4000 V95.0 % >95.0 % coverage goal and 100 % of adapted plans met OAR dose constraints. Median follow up was 6.6 months. Only 1 patient experienced acute grade 3+ toxicity directly attributable to radiation. Only 1 patient experienced late grade 3+ toxicity directly attributable to radiation. Conclusions: Daily CT-based OART was associated with significantly reduced dose OARs while achieving superior PTV coverage. Given the relatively quick total treatment time, radiation delivery was generally well tolerated and easily incorporated into the clinic workflow. Our initial clinical experience demonstrates OART allows for safe dose escalation in the treatment of PDAC.

Objective: Negative psychological beliefs like fear avoidance and catastrophizing can interfere with exercise engagement in people with knee osteoarthritis (OA). Mindfulness, when integrated with exercise, could potentially address both psychological and physical impairments. Our objectives were to optimize and assess the feasibility of a novel telehealth, group-based mindful exercise intervention for people with knee OA. Methods: We conducted a decentralized randomized controlled trial where participants (n ​= ​40) with symptomatic knee OA were randomized into mindful exercise (n ​= ​21) or exercise-only (n ​= ​19) groups. Both groups received supervised group-based interventions weekly for 8-weeks via Zoom. Primary outcomes were safety, fidelity, and feasibility of the mindful exercise intervention. Participants completed patient-reported outcomes (PRO) for pain, function, and psychological measures at baseline, week-8, and week-14. Results: Participants were from 21 US states; >90% identified as having White race, 16% were from rural areas, and approximately 40% had an annual income < $50,000. At 8-weeks, mindful exercise and exercise groups had retention rates of 86% (18/21) and 100% (19/19), and attendance was 54% (11.4/21) and 68% (13/19) respectively. There were no adverse events in the mindful exercise group and four in the exercise group related to exacerbation of knee pain. Preliminary findings showed numerically larger improvements in several PROs for the mindful exercise group. Conclusion: An 8-week telehealth, group-based, mindful exercise intervention was safe for people with knee OA. Our decentralized approach was feasible in terms of recruitment and retention. Further refinement is needed to improve intervention attendance and participant diversity.

Objectives: Total hip arthroplasty is a successful procedure for treating advanced osteoarthritis (OA). Metal bearing surfaces remain one of the most widely implanted prosthesis, however approximately 10% of patients develop adverse local tissue reactions (ALTRs), namely lymphocytic predominant soft tissue reaction with or without necrosis and osteolysis resulting in high revision rates. The mechanism(s) for these reactions remains unclear although T lymphocyte mediated type IV hypersensitivity to cobalt (Co) and chromium (Cr) ions have been described. The purpose of this study was to determine the prolonged effects of Co and Cr metal ions on synovial fibroblasts to better understand the impact of the synovial membrane in the development of ALTRs. Methods: Human synovial fibroblast-like cells were isolated from donors undergoing arthroplasty. DNA content and Alamar blue assay were used to determine cellular viability against exposure to Co and Cr. A beta-galactosidase assay was used to determine the development of cellular senescence. Western blotting and RT-qPCR were employed to determine changes in senescent associated secretory factors, signaling and anti-oxidant enzyme expression. A fluorescent assay was used to measure accumulation of hydrogen peroxide. Results: We demonstrate that prolonged cobalt exposure results in a downregulation of the enzyme catalase resulting in cytosolic accumulation of hydrogen peroxide, decreased Akt activity and cellular senescence. Senescent fibroblasts demonstrated upregulation of proinflammatory cytokines IL-1β and TNFα in addition to the neurotrophic factor NGF. Conclusion: Our results provide evidence that metal ions induce a senescent associated secretory phenotype in synovial fibroblasts that could contribute to the development of adverse local tissue reactions.

Abstract The chemokine CXCL12 promotes glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating vasculogenesis. Here we report outcomes of the dose-escalation part of GLORIA (NCT04121455), a phase I/II trial combining RT and the CXCL12-neutralizing aptamer olaptesed pegol (NOX-A12; 200/400/600 mg per week) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose (MTD), recommended phase II dose (RP2D), NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life (QOL), median progression-free survival (PFS), 6-months PFS and overall survival (OS). Treatment was safe with no dose-limiting toxicities or treatment-related deaths. The MTD has not been reached and, thus, 600 mg per week of NOX-A12 was established as RP2D for the ongoing expansion part of the trial. With increasing NOX-A12 dose levels, a corresponding increase of NOX-A12 plasma levels was observed. Of ten patients enrolled, nine showed radiographic responses, four reached partial remission. All but one patient (90%) showed at best response reduced perfusion values in terms of relative cerebral blood volume (rCBV). The median PFS was 174 (range 58-260) days, 6-month PFS was 40.0% and the median OS 389 (144-562) days. In a post-hoc exploratory analysis of tumor tissue, higher frequency of CXCL12+ endothelial and glioma cells was significantly associated with longer PFS under NOX-A12. Our data imply safety of NOX-A12 and its efficacy signal warrants further investigation.

Abstract Elevated intracellular sodium Nai adversely affects mitochondrial metabolism and is a common feature of heart failure. The reversibility of acute Na induced metabolic changes is evaluated in Langendorff perfused rat hearts using the Na/K ATPase inhibitor ouabain and the myosin-uncoupler para-aminoblebbistatin to maintain constant energetic demand. Elevated Nai decreases Gibb’s free energy of ATP hydrolysis, increases the TCA cycle intermediates succinate and fumarate, decreases ETC activity at Complexes I, II and III, and causes a redox shift of CoQ to CoQH2, which are all reversed on lowering Nai to baseline levels. Pseudo hypoxia and stabilization of HIF-1α is observed despite normal tissue oxygenation. Inhibition of mitochondrial Na/Ca-exchange with CGP-37517 or treatment with the mitochondrial ROS scavenger MitoQ prevents the metabolic alterations during Nai elevation. Elevated Nai plays a reversible role in the metabolic and functional changes and is a novel therapeutic target to correct metabolic dysfunction in heart failure.

Abstract Background Therapeutic drug monitoring (TDM) of anti-infectives such as linezolid is routinely performed in blood of intensive care unit (ICU) patients to optimize target attainment. However, the concentration at the site of infection is considered more important for a successful therapy. Until now, bronchoalveolar lavage (BAL) is the gold standard to measure intrapulmonary concentrations of anti-infective agents. However, it is an invasive method and unsuitable for regular TDM. The aim of this proof-of-concept study was to investigate whether it is possible to reliably determine the intrapulmonary concentration of linezolid from endotracheal aspiration (ENTA). Methods Intubated ICU patients receiving 600 mg intravenous linezolid twice daily were examined in steady state. First, preliminary experiments were performed in six patients to investigate which patients are suitable for linezolid measurement in ENTA. In a second step, trough and peak linezolid concentrations of plasma and ENTA were determined in nine suitable patients. Results Linezolid can validly be detected in ENTA with viscous texture and > 0.5 mL volume. The mean (SD) linezolid trough concentration was 2.02 (1.27) mg/L in plasma and 1.60 (1.36) mg/L in ENTA, resulting in a median lung penetration rate of 104%. The mean (SD) peak concentration in plasma and ENTA was 10.77 (5.93) and 4.74 (2.66) mg/L. Conclusions Linezolid can validly be determined in ENTA with an adequate texture and volume. The penetration rate is comparable to already published BAL concentrations. This method might offer a simple and non-invasive method for TDM at the site of infection “lung”. Due to promising results of the feasibility study, comparison of ENTA and BAL in the same patient should be investigated in a further trial.

Abstract Castellaniella species have been isolated from a variety of mixed-waste environments including the nitrate and multiple metal-contaminated subsurface at the Oak Ridge Reservation (ORR). Previous studies examining microbial community composition and nitrate removal at ORR during biostimulation efforts reported increased abundances of members of the Castellaniella genus concurrent with increased denitrification rates. Thus, we asked how genomic and abiotic factors control the Castellaniella biogeography at the site to understand how these factors may influence nitrate transformation in an anthropogenically impacted setting. We report the isolation and characterization of several Castellaniella strains from the ORR subsurface. Five of these isolates match at 100% identity (at the 16S rRNA gene V4 region) to two Castellaniella amplicon sequence variants (ASVs), ASV1 and ASV2, that have persisted in the ORR subsurface for at least 2 decades. However, ASV2 has consistently higher relative abundance in samples taken from the site and was also the dominant blooming denitrifier population during a prior biostimulation effort. We found that the ASV2 representative strain has greater resistance to mixed metal stress than the ASV1 representative strains. We attribute this resistance, in part, to the large number of unique heavy metal resistance genes identified on a genomic island in the ASV2 representative genome. Additionally, we suggest that the relatively lower fitness of ASV1 may be connected to the loss of the nitrous oxide reductase (nos) operon (and associated nitrous oxide reductase activity) due to the insertion at this genomic locus of a mobile genetic element carrying copper resistance genes. This study demonstrates the value of integrating genomic, environmental, and phenotypic data to characterize the biogeography of key microorganisms in contaminated sites.

Abstract Background Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann’s procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6 years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P

Abstract The use of head‐mounted augmented reality (AR) for surgeries has grown rapidly in recent years. AR aids in intraoperative surgical navigation through overlaying three‐dimensional (3D) holographic reconstructions of medical data. However, performing AR surgeries on complex areas such as the head and neck region poses challenges in terms of accuracy and speed. This study explores the feasibility of an AR guidance system for resections of positive tumour margins in a cadaveric specimen. The authors present an intraoperative solution that enables surgeons to upload and visualize holographic reconstructions of resected cadaver tissues. The solution involves using a 3D scanner to capture detailed scans of the resected tissue, which are subsequently uploaded into our software. The software converts the scans of resected tissues into specimen holograms that are viewable through a head‐mounted AR display. By re‐aligning these holograms with cadavers with gestures or voice commands, surgeons can navigate the head and neck tumour site. This workflow can run concurrently with frozen section analysis. On average, the authors achieve an uploading time of 2.98 min, visualization time of 1.05 min, and re‐alignment time of 4.39 min, compared to the 20 to 30 min typical for frozen section analysis. The authors achieve a mean re‐alignment error of 3.1 mm. The authors’ software provides a foundation for new research and product development for using AR to navigate complex 3D anatomy in surgery.

Abstract Introduction Long-acting lipoglycopeptides such as dalbavancin may have utility in patients with Gram-positive bloodstream infections (BSI), particularly in those with barriers to discharge or who require prolonged parenteral antibiotic courses. A retrospective cohort study was performed to provide further multicenter real-world evidence on dalbavancin use as a sequential therapy for Gram-positive BSI. Methods One hundred fifteen patients received dalbavancin with Gram-positive BSI, defined as any positive blood culture or diagnosed with infective endocarditis, from 13 centers geographically spread across the United States between July 2015 and July 2021. Results Patients had a mean (SD) age of 48.5 (17.5) years, the majority were male (54%), with many who injected drugs (40%). The most common infection sources (non-exclusive) were primary BSI (89%), skin and soft tissue infection (SSTI) (25%), infective endocarditis (19%), and bone and joint infection (17%). Staphylococcus aureus accounted for 72% of index cultures, coagulase-negative Staphylococcus accounted for 18%, and Streptococcus species in 16%. Dalbavancin started a median (Q1–Q3) of 10 (6–19) days after index culture collection. The most common regimen administered was dalbavancin 1500 mg as one dose for 50% of cases. The primary outcome of composite clinical failure occurred at 12.2%, with 90-day mortality at 7.0% and 90-day BSI recurrence at 3.5%. Conclusions Dalbavancin may serve as a useful tool in facilitating hospital discharge in patients with Gram-positive BSI. Randomized controlled trials are anticipated to validate dalbavancin as a surrogate to current treatment standards.

Abstract Pyrolysis is one method for treating sewage sludge, particularly in remote areas or decentralised systems. The end product of pyrolysis, sludge-char, can serve as a soil improver. However, there is a lack of comprehensive data on the organic pollutants’ behaviour in sludge-char. In our work, we focused on the behaviour of per- and polyfluoroalkyl substances (PFASs). Sludge was pyrolyzed at 200–700 °C to determine the minimum safe temperature for effective PFASs removal. It is important to note that PFASs may not only be mineralized but also cleaved to unanalyzed PFASs and other organofluorinated substances. To address this issue, we incorporated additional measurements of organic fluorine in the experiment using combustion ion chromatography (CIC). Due to the inherent heterogeneity of sludge, containing a variety of pollutants and their precursors, we conducted pyrolysis on artificially contaminated sand. This allowed us to assess and compare the behaviour of PFASs in a homogeneous matrix. Based on our analyses, we determined that a temperature greater than 400 °C is imperative for effective PFASs and organic fluorine removal. The results were verified by analyzing samples from a commercial sludge pyrolysis unit at the Bohuslavice-Trutnov WWTP, which confirmed our measurements. In light of these results, it becomes evident that sludge pyrolysis below 400 °C is unsuitable for PFAS removal from sewage sludge. Graphical Abstract

Abstract Plant diversity effects on community productivity often increase over time. Whether the strengthening of diversity effects is caused by temporal shifts in species-level overyielding (i.e., higher species-level productivity in diverse communities compared with monocultures) remains unclear. Here, using data from 65 grassland and forest biodiversity experiments, we show that the temporal strength of diversity effects at the community scale is underpinned by temporal changes in the species that yield. These temporal trends of species-level overyielding are shaped by plant ecological strategies, which can be quantitatively delimited by functional traits. In grasslands, the temporal strengthening of biodiversity effects on community productivity was associated with increasing biomass overyielding of resource-conservative species increasing over time, and with overyielding of species characterized by fast resource acquisition either decreasing or increasing. In forests, temporal trends in species overyielding differ when considering above- versus belowground resource acquisition strategies. Overyielding in stem growth decreased for species with high light capture capacity but increased for those with high soil resource acquisition capacity. Our results imply that a diversity of species with different, and potentially complementary, ecological strategies is beneficial for maintaining community productivity over time in both grassland and forest ecosystems.