The effect of adsorbent textural and functional properties on model naphthenic acid adsorption.

Naphthenic acids, NAs, are a major contaminant of concern and a focus of much research around remediation of oil sand process affected waters, OSPW. Using activated carbon adsorbents are an attractive option given their low cost of fabrication and implementation. A deeper evaluation of the effect NA structural differences have on uptake affinity is warranted. Here we provide an in-depth exploration of NA adsorption including many more model NA species than have been assessed previously with evaluation of adsorption kinetics and isotherms at the relevant alkaline pH of OSPW using several different carbon adsorbents with pH buffering to simulate the behaviour of real OSPW. Uptake for the NA varied considerably regardless of the activated carbon used, ranging from 350 mg/g to near zero highlighting recalcitrant NAs. The equilibrium data was explored to identify structural features of these species and key physiochemical properties that influence adsorption. We found that certain NA will be resistant to adsorption when hydrophobic adsorbents are used. Adsorption isotherm modelling helped explore interactions occurring at the interface between NA and adsorbent surfaces. We identified the importance of NA hydrophobicity for activated carbon uptake. Evidence is also presented that indicates favorable hydrogen bonding between certain NA and surface site hydroxyl groups, demonstrating the importance of adsorbent surface functionality for NA uptake. This research highlights the challenges associated with removing NAs from OSPW through adsorption and also identifies how adsorbent surface chemistry modification can be used to increase the removal efficiency of recalcitrant NA species.

Deciphering intersystem crossing and energy transfer mechanisms in a nonacoordinated ternary europium(iii) complex: a combined spectroscopic and theoretical study.

A monochromatic red emitting nonacoordinate organoeuropium complex with the formula [Eu(hfaa)3(Ph-TerPyr)] (Eu-1) incorporating hexafluoroacetylacetone (hfaa) primary ligands and a tridentate 4'-phenyl-2,2':6',2''-terpyridine (Ph-TerPyr) ancillary ligand has been synthesized. The complex was characterized by analytical and spectroscopic methods, and its structure was established by single crystal X-ray diffraction (SC-XRD) analysis at low temperature, which explicitly confirms that the coordination sphere is composed of a EuO6N3 core. Under the UV excitation, Eu-1 displayed typical red emission in solution with a long-excited state lifetime (τ obs = 1048.06 ± 9.39 µs) with a good photoluminescence quantum yield (Q L Eu = 41.14%). We have utilized pump-probe ultrafast transient absorption spectroscopy in tandem with the time-dependent density functional theory (TD-DFT) and the Lanthanide Luminescence Software Package (LUMPAC) to explore the intricate photophysical event that occurs in the vicinity of the ligands of Eu-1 sensitized photoluminescence (PL).

Global and regional prediction of heterakidosis population prevalence in extensive backyard chickens in low-income and middle-income countries.

Extensive backyard chickens are one of the most common production systems in low-income and middle-income countries (LMICs). In this production system, chickens are exposed to infectious forms of parasites as a result of the outdoor access and scavenging behaviour. Heterakis gallinarum is one of the most common nematode parasites present in the environment, and estimating its global and regional prevalence is essential for attributing the economic losses in extensive backyard chickens. The objective of this study is to predict the prevalence of heterakidosis in extensive backyard chickens at global and regional levels in LMICs using regression imputation methods. A binomial random effect model was developed using empirical data on heterakidosis prevalence and climatic factors as main predictors. Prevalence data were then imputed in all regions based on the regression model. Global and country prevalence were estimated based on regional predictions and their beta distributions. Minimum precipitation, minimum temperature and maximum temperature were selected as significant predictors. The population prevalence of heterakidosis was 0.24 (0.19-0.29). Countries with continental and dry climates had a higher mean prevalence, whereas countries with tropical climates had a lower mean prevalence of heterakidosis. As more empirical data on heterakidosis prevalence become available, this model and predictions should be redefined and updated to capture a more representative association and increase the accuracy of the predictions. The results of this study can be used to attribute the economic losses of extensive backyard chickens, taking into account a holistic approach as promoted by the GBADs programme and therefore, to identify which diseases are more costly to backyard farmers. Furthermore, results can be also served as a proxy for the risk of histomoniasis in extensive backyard chickens.

Academic psychiatry is everyone's business.

This editorial considers the value and nature of academic psychiatry by asking what defines the specialty and psychiatrists as academics. We frame academic psychiatry as a way of thinking that benefits clinical services and discuss how to inspire the next generation of academics.

A supply-based scoring approach to account for biological disadvantages in accessing lung transplant.

BACKGROUND: The lung Composite Allocation Score (CAS) accounts separately for biological disadvantages stemming from candidate blood type and height using consensus-derived heuristics, which do not reflect the true supply of compatible organs available to candidates with specific combinations of blood type and height. Here, we develop an alternative CAS biological disadvantages subscore using a novel measure of donor supply. METHODS: Using Scientific Registry of Transplant Recipients data from February 19, 2015 to September 1, 2021, we modeled daily distance-adjusted supply of compatible donors, as a function of candidate blood type, height, and diagnosis group, using Poisson rate regression and applied the model to create a 10-point supply-based subscore. Substituting this subscore in place of the 10 total points allocated to blood type and height in CAS created a "Supply-Adjusted CAS". We simulated population outcomes under Supply-Adjusted CAS, original CAS (March 2023) and "ABO Modified" CAS (September 2023). RESULTS: The supply-based subscore was more responsive to variations in candidate blood type, height, and diagnosis group than corresponding CAS or ABO-Modified CAS subscores. In simulation, waitlist mortality improved from 13.95 per 100 waitlist years under CAS and 14.12 under ABO-Modified CAS to 13.09 under Supply-Adjusted CAS. Transplant rates improved from 121.6 and 126.2 under CAS and ABO-Modified CAS, respectively, to 128.8 under Supply-Adjusted CAS. Height disparities improved substantially, while blood type disparities grew slightly relative to ABO-Modified CAS. CONCLUSIONS: Supply-Adjusted CAS may improve lung transplant population outcomes overall while providing a more empirically based method to address equity.

Lead Acetate Exposure and Cerebral Amyloid Accumulation: Mechanistic Evaluations in APP/PS1 Mice.

BACKGROUND: The role of environmental factors in Alzheimer's disease (AD) pathogenesis remains elusive. Mounting evidence suggests that acute and past exposure to the environmental toxicant lead (Pb) is associated with longitudinal decline in cognitive function, brain atrophy, and greater brain ß-amyloid (Aß) deposition. However, the nature of Pb-induced amyloid deposition and how it contributes to AD development remain unclear. OBJECTIVES: This study investigates the role of Pb in the pathogenesis of cerebral amyloid angiopathy (CAA) and whether plasminogen activator inhibitor-1 (PAI-1) contributes to this process in the APP/PS1 mouse model. METHODS: Female APP/PS1 mice at 8 wk of age were administered either 50mg/kg Pb-acetate (PbAc) (i.e., 27mg Pb/kg) or an equivalent molar concentration of sodium acetate (NaAc) via oral gavage once daily for 8 wk. Amyloid deposition and vascular amyloid were determined by immunostaining. In addition, Aß perivascular drainage, vascular binding assay, and microglial endocytosis were examined to determine underlying mechanisms. Furthermore, magnetic resonance imaging demyelination imaging was performed in vivo measure the level of demyelination. Finally, Y-maze and Morris water maze tests were assessed to evaluate the cognitive function of mice. RESULTS: APP/PS1 mice (an AD mice model) exposed to PbAc demonstrated more vascular amyloid deposition less neocortical myelination, and lower cognitive function, as well as greater vascular binding to Aß40, higher Aß40/Aß42 ratios, strikingly lower Aß40 levels in the perivascular drainage, and microglial endocytosis. Importantly, exposure to a specific PAI-1 inhibitor, tiplaxtinin, which previously was reported to lower CAA pathology in mice, resulted in less CAA-related outcomes following PbAc exposure. DISCUSSION: Our findings suggest that PbAc induced CAA/AD pathogenesis via the PAI-1 signaling in the APP/PS1 mouse model, and the inhibition of PAI-1 could be a potential therapeutic target for PbAc-mediated CAA/AD disorders. https://doi.org/10.1289/EHP14384.

Predictors of death without prior appropriate therapy in ICD recipients: the comorbidities, frailty and functional status (COMFFORT study).

OBJECTIVE: Most patients who have an implantable cardioverter-defibrillator (ICD) implant do not receive life-prolonging therapy from it. Little research has been undertaken to determine which patients benefit the least from ICD therapy. As patients age and accumulate comorbidities, the risk of death increases and the benefit of ICDs diminishes. We sought to evaluate the impact of comorbidity, frailty, functional status on death with no prior appropriate ICD therapy. METHODS: A prospective, multicentre, observational study involving 12 English hospitals was undertaken. Patients were eligible for inclusion for the study if they were scheduled to have a de novo, upgrade to or replacement of a transvenous or subcutaneous ICD or cardiac resynchronisation therapy device and defibrillator (CRT-D). Baseline characteristics were collected. Participants were asked to complete a frailty assessment (Fried score) and a functional status questionnaire (EuroQol 5-Dimension 5-Level (EQ-5D-5L)). The Charlson Comorbidity Index was calculated. Patients were prospectively followed up for 2.5 years. The primary outcome was death with no prior appropriate therapy. RESULTS: In total, 675 patients were enrolled, mean age 65.7 (IQR 65-75) years. A total of 63 patients (9.5%) died during follow-up, 58 without receiving appropriate ICD therapy. Frailty was present in 86/675 (12.7%) and severe comorbidity in 69/675 (10.2%). Multivariate predictors of death with no appropriate therapy were identified and a risk score comprising frailty, comorbidity, increasing age, estimated glomerular filtration rate and EQ-5D-5L was developed. CONCLUSION: Comorbidities, frailty and the EQ-5D-5L score are powerful, independent predictors of death with no prior appropriate therapy in ICD/CRT-D recipients.

Physicochemical and biocompatibility characterisation of a 3D lyophilised platelet-rich fibrin scaffold for cleft lip and palate repair.

Craniofacial bone defects result from various disorders such as trauma, congenital malformations and infections. Cleft lip and palate are the most prevalent congenital craniofacial birth defect in humans. Growth factors (GFs) are soluble proteins secreted by cells that regulate various cellular processes and tissue regeneration. At present, developing three-dimensional scaffolds for delivering GFs to the site of injury has become an important aspect in craniofacial bone regeneration. This study aims to develop a novel 3D bone substitute using lyophilized-platelet-rich fibrin (LyPRF) biocomposite scaffolds for potential application for CLP repair. Collagen (C), bioglass (BG), and LyPRF were used to fabricate a biocomposite (C-BG-LyPRF) scaffold. The physical, chemical, and biocompatibility properties of the scaffold were evaluated. The C-BG-LyPRF scaffold demonstrated a mean pore diameter of 146 µm within a porosity of 87.26%. The FTIR spectra verified the presence of am-ide I, II, and III functional groups. The inorganic phase of the C-BG-LyPRF scaffold was composed of sodium, calcium, silicon, and phosphorus, as determined by EDX analysis. Furthermore, C-BG-LyPRF scaffold was biocompatible with MC3T3-E1 cells in both the Live/Dead and prolif-eration assays. Data demonstrate the developed C-BG-LyPRF scaffold exhibits biomimetic and biocompatibility properties, establishing it as a promising biomaterial for craniofacial regeneration.

Bone Marrow and Peripheral Blood Mononuclear Cell Phenotype Changes after Cultivation and Autologous Infusion in Patients with Primary Biliary Cholangitis.

Background: Primary biliary cholangitis (PBC) is a condition affecting the liver and immune system. In this study, the impact of autologous bone marrow-derived mononuclear cell (BM-MNC) transplantation on PBC patients was investigated. Methods: Sixteen eligible PBC patients participated at the National Scientific Medical Center in Astana, Kazakhstan, between 2017 and 2022, and BM-MNCs were harvested from their anterior iliac crest. After isolating and cultivating the BM-MNCs, they were infused back into the patient's peripheral veins. Changes in BM-MNC and peripheral blood mononuclear cell (PB-MNC) phenotypes were assessed before and after a 24-hour cultivation period and 72 hours post-transplantation. We monitored liver function parameters over 6-month intervals and conducted flow cytometry analysis to assess CD markers on BM-MNCs before and after cultivation and PB-MNCs before and after transplantation. Statistical analysis included the Friedman test for liver parameters and the Wilcoxon signed-rank test for BM-MNC and PB-MNC comparisons. Results: Our findings revealed significant reductions in liver function tests after multiple transplantations. Flow cytometry analysis before and after a 24-hour culture and autologous BM-MNC infusion revealed the expansion of specific cell populations, with significant increases in CD3+, CD4+, CD16+, CD20+, CD25+, CD34+, CD105+, CD73+, СD117+, and CD34+populations, while CD4+25+, CD34+105+, and CD4+FOXP3+ populations decreased. Interestingly, a contradictory finding was observed with a decrease in bone marrow CD34+105+ cell lines (P=0.03) alongside an increase in peripheral CD34+105+ population (P=0.03). Conclusion: In summary, our study shows that BM-MNC transplantation in PBC patients leads to changes in immune cell populations and liver function. These findings suggest potential therapeutic applications of BM-MNC transplantation in managing PBC and offer insights into the dynamics of immune cells associated with this treatment approach.

A multiple x-ray-source array (MXA) system with a planar two-dimensional source distribution for digital breast tomosynthesis.

BACKGROUND: Digital breast tomosynthesis (DBT) has outpaced digital mammography in clinical adoption in the United States; however, substantial technological limitations remain to image quality in DBT, including undersampling from a one-dimensional (1D) scan geometry, x-ray source motion during acquisition, and patient motion artifacts from long exam times. PURPOSE: A thermionic cathode x-ray system employing two-dimensional (2D, planar) multiple x-ray-source arrays (MXA) is proposed to improve DBT image quality. METHODS: A 1D MXA, consisting of a linear array of thermionic cathodes was used to simulate a 2D MXA. The 1D MXA included 11 focal spots separated by a distance of Δ d ${{\Delta}}d$  = 23 mm. The 11 cathodes were paired with 11 molybdenum 50 mm diameter anode disks, mounted on a rotating shaft within a single vacuum enclosure. Image quality was investigated as a function of MXA configuration by integrating the 1D MXA with a 200 × 250 mm2 flat panel detector at a source-to-detector distance of 630 mm, resulting in a 20° tomographic arc. To simulate a 2D MXA, the detector (with phantom) was translated orthogonally to the linear array by a distance ( δ $\delta $ ) ranging from δ $\delta $  = 0 mm (conventional 1D) to δ $\delta $  = 57 mm. All sources operated at 30 kV with 80 mA and 4.5 mAs/pulse, yielding ∼100 mAs per DBT dataset. DBT reconstructions involved 22 projections and used filtered backprojection with a ramp and Hann apodization filter. Volumetric reconstructions for each source were weighted by sampling differences between sources, and averaged. Image quality was assessed in terms of contrast-to-noise ratio (CNR), background clutter noise and power spectrum, and slice sensitivity profile (SSP) using a set of physical phantoms, including: (i) contrast-detail signals coupled to spherical clutter (PMMA in air); (ii) an SSP phantom; (iii) a commercial "breast" phantom (CIRS BR3D, Sun Nuclear, Norfolk, VA); and (iv) bovine muscle. RESULTS: Background clutter noise amplitude reduced monotonically from the 1D MXA (σclutter = 5.9 A.U., δ $\delta $  = 0 mm) and 2D MXA arrays with increasing δ $\delta $ , with statistical significance between the 1D MXA and 2D MXA with δ $\delta $  = 57 mm (σclutter = 5.0 A.U., p < 0.001). The contrast-detail/clutter phantom demonstrated CNR from the 2D MXA (δ  = 57 mm) outperforming the 1D MXA in all combinations of contrast and detail. 2D power spectrum analysis of clutter demonstrated a pronounced Fourier domain null cone for the 1D MXA in the anterior field-of-view (away from the 1D MXA position), whereas the 2D MXA geometry (δ = 57 mm) did not exhibit the null cone. The SSP was 15%-50% narrower (FWHM) for the 2D versus the 1D geometry, across all reconstruction setups. CONCLUSIONS: The advantages of a 2D source geometry for DBT imaging were demonstrated quantitatively compared to a conventional 1D line of x-ray sources. The improvement in the 2D geometry was attributed both to improved Fourier domain sampling and reduced SSP. We conclude that 2D MXA sources have the potential to substantially improve DBT imaging in comparison to existing commercial DBT systems.

Intima media thickness of the carotid artery in primary antiphospholipid syndrome: A systematic review and meta-analysis.

BACKGROUND: Primary antiphospholipid syndrome (PAPS) has been associated with an increase in clinical events associated with atherosclerotic vascular disease. Intima media thickness (IMT) of carotid arteries is a surrogate marker of atherosclerotic vascular disease. OBJECTIVES: To conduct a systematic review and meta-analysis of studies evaluating IMT and their clinical correlates in PAPS. METHODS: Systematic search of EMBASE and PubMed databases from January 2000 to December 2023; we employed random effect meta-analyses for continuous outcomes and Peto's odds ratio for rare events. RESULTS: The meta-analysis included 21 studies (20 case control and 1 cohort) showing that PAPS patients (n = 1103) had thicker IM than controls (n = 832) (p < 0.0001) with wide heterogeneity (I2 = 86.9 %); PAPS patients (n = 782) also had a greater pooled prevalence of carotid plaques than controls (n = 537) (13.1 % vs 2.97 %, p < 0.0001). A sensitivity analysis by meta-regression indicated that mean age, gender, disease duration, lipid profile, blood pressures, smoking and statin use all explained the heterogeneity variance; a sensitivity analysis by subgroups confirmed smoking status and statin use as explanatory variables with the addition of ethnicity. CONCLUSION: Atherosclerosis of the carotid artery represents a clinical feature of PAPS in relation to the traditional risk factors and to statin use. Minimising the atherogenic risk with statins could reduce the late arterial atherothrombotic risks of PAPS.

SEC31a-ATG9a Interaction Mediates the Recruitment of COPII Vesicles for Autophagosome Formation.

Autophagy plays an important role in determining stem-cell differentiation. During the osteogenic differentiation of mesenchymal stem cells (MSCs), autophagosome formation is upregulated but the reason is unknown. A long-standing quest in the autophagy field is to find the membrane origin of autophagosomes. In this study, cytoplasmic coat protein complex II (COPII) vesicles, endoplasmic reticulum-derived vesicles responsible for the transport of storage proteins to the Golgi, are demonstrated to be a critical source of osteoblastic autophagosomal membrane. A significant correlation between the number of COPII vesicle and the autophagy level is identified in the rat bone tissues. Disruption of COPII vesicles restrained osteogenesis and decreased the number and size of autophagosomes. SEC31a (an outer coat protein of COPII vesicle) is found to be vital to regulate COPII vesicle-dependent autophagosome formation via interacting with ATG9a of autophagosomal seed vesicles. The interference of Sec31a inhibited autophagosome formation and osteogenesis in vitro and in vivo. These results identified a novel mechanism of autophagosome formation in osteogenic differentiation of stem cells and identified SEC31a as a critical protein that mediates the interplay between COPII and ATG9a vesicles. These findings broaden the understanding of the regulatory mechanism in the osteogenic differentiation of MSCs.

Sentiment analysis of letters of recommendation for a U.S. pain medicine fellowship from 2020 to 2023.

OBJECTIVES: Letters of recommendation (LORs) are an important part of pain medicine fellowship applications that may be subject to implicit bias by the letter's author. This study evaluated letters of recommendation for applications to pain medicine fellowships in the United States to characterize biases and differences among applicants over four application cycles. METHODS: This was a retrospective single-site cohort study. De-identified LORs were collected from 2020 to 2023 from one institution. The Valence Aware Dictionary and sEntiment Reasoner (VADER) natural language processing package scored positive LOR sentiment. In addition, the deep learning tool, Empath, scored LORs for 15 sentiments. Wilcoxon rank-sum and one-way ANOVA tests compared scores between applicant demographics: gender, race, medical school type, residency specialty, and chief resident status, as well as letter writers' academic position. RESULTS: Nine hundred and sixty-four applications were studied over four application cycles. Program directors wrote fewer words (p = 0.020) and less positively (p < 0.001) compared to department chairs and letter writers with neither position. Department chairs wrote with less "negative emotion" compared to both program directors and writers with neither position (p < 0.001). Anesthesiologist applicants received more letters highlighting "achievement" (p < 0.001) while PM&R applicants submitted letters with less "negative emotion" (p < 0.001) compared to other specialties. Chief residents' letters scored higher in "leader" sentiment (p < 0.001) and lower in "negative emotion" (p < 0.001). DISCUSSION: Linguistic content did not favor certain genders or races over others. However, disparities in LORs do exist depending on an applicant's specialty and chief resident status, as well as the academic status of the letter writer.

Institution-Wide Moral Distress Among Nurses.

BACKGROUND: Moral distress is the inability to do the right thing due to imposed constraints. OBJECTIVE: Explore the presence of moral distress among nurses. METHODS: A quantitative, exploratory, cross-sectional study at a level 1 trauma center using the Measure of Moral Distress for Healthcare Professionals (MMD-HP). RESULTS: Ninety-seven nurses completed the MMD-HP. The top 3 items contributing to moral distress included inadequate staffing, inadequate resources, and lack of administrative support. Nurses who considered leaving had more moral distress. Moral distress explained 28.5% of the variance associated with nurses' "intent to leave" and "primary unit" (P < 0.001). Moral distress for nurses 40 to 49 years of age was higher compared with nurses 50 years or older. CONCLUSIONS: Moral distress involved deficiencies in staffing, resources, and administrative support. Research should explore interventions to mitigate moral distress among nurses by promoting safe staffing levels, the provision of adequate resources, and increased administrative support.

The visual experience dataset: Over 200 recorded hours of integrated eye movement, odometry, and egocentric video.

We introduce the Visual Experience Dataset (VEDB), a compilation of more than 240 hours of egocentric video combined with gaze- and head-tracking data that offer an unprecedented view of the visual world as experienced by human observers. The dataset consists of 717 sessions, recorded by 56 observers ranging from 7 to 46 years of age. This article outlines the data collection, processing, and labeling protocols undertaken to ensure a representative sample and discusses the potential sources of error or bias within the dataset. The VEDB's potential applications are vast, including improving gaze-tracking methodologies, assessing spatiotemporal image statistics, and refining deep neural networks for scene and activity recognition. The VEDB is accessible through established open science platforms and is intended to be a living dataset with plans for expansion and community contributions. It is released with an emphasis on ethical considerations, such as participant privacy and the mitigation of potential biases. By providing a dataset grounded in real-world experiences and accompanied by extensive metadata and supporting code, the authors invite the research community to use and contribute to the VEDB, facilitating a richer understanding of visual perception and behavior in naturalistic settings.

A Standard Approach to Project-Based Learning in a Clinical Informatics Fellowship.

BACKGROUND: The Accreditation Council for Graduate Medical Education suggests that Clinical Informatics (CI) fellowship programs foster broad skills, which include collaboration and project management. However, they do not dictate how to best accomplish these learning objectives. OBJECTIVES: This study aimed to describe a standard approach to project-based learning for CI, to share its implementation, and to discuss lessons learned. METHODS: We created a standard approach to project-based learning based on concepts from adult learning theory, the project life cycle framework, the Toyota Production System, and Improvement Science. RESULTS: With this standard approach in place, we learned how best to support fellows in its use. In addition to this approach to supporting needs assessment, risk/change management, implementation, and evaluation/improvement skills, we found the need to develop fellow skills in collaboration, leadership, and time management/managing up. Supported by project-based learning using this standard approach, and with targeted project selection to meet topic-based learning objectives, fellows reached the ability to practice independently in 15 to 21 months. DISCUSSION: Fellows are uniquely positioned to ensure the success of projects due to their increased availability and protected time compared with attendings. They are readily available for project teams to draw upon their expertise with clinical workflows and understanding of technological solutions. Project-based learning addressing organizational priorities complements fellow project management coursework and improves fellows' ability to function successfully in large, complex, and dynamic organizations. Exposing fellows to contemporary problems, then addressing them through projects, provides fellows with up-to-date applied informatics knowledge. CONCLUSION: Project-based learning can ensure that many general CI learning objectives are supported inherently. It reinforces project management teachings, while providing fellows with a marketable project portfolio to aid with future job applications. Having projects tightly aligned with organizational priorities supports ongoing investment in fellowship programs.

Amoebic encephalitis within Australia.

Granulomatous amoebic encephalitis is a rare but likely under-recognised form of subacute, usually fatal, encephalitis. We present an illustrative case report and literature review of Australian cases, summarising clinical features, diagnostic methods, treatment and outcomes.

Aligning with the 3Rs: alternative models for research into muscle development and inherited myopathies.

Inherited and acquired muscle diseases are an important cause of morbidity and mortality in human medical and veterinary patients. Researchers use models to study skeletal muscle development and pathology, improve our understanding of disease pathogenesis and explore new treatment options. Experiments on laboratory animals, including murine and canine models, have led to huge advances in congenital myopathy and muscular dystrophy research that have translated into clinical treatment trials in human patients with these debilitating and often fatal conditions. Whilst animal experimentation has enabled many significant and impactful discoveries that otherwise may not have been possible, we have an ethical and moral, and in many countries also a legal, obligation to consider alternatives. This review discusses the models available as alternatives to mammals for muscle development, biology and disease research with a focus on inherited myopathies. Cell culture models can be used to replace animals for some applications: traditional monolayer cultures (for example, using the immortalised C2C12 cell line) are accessible, tractable and inexpensive but developmentally limited to immature myotube stages; more recently, developments in tissue engineering have led to three-dimensional cultures with improved differentiation capabilities. Advances in computer modelling and an improved understanding of pathogenetic mechanisms are likely to herald new models and opportunities for replacement. Where this is not possible, a 3Rs approach advocates partial replacement with the use of less sentient animals (including invertebrates (such as worms Caenorhabditis elegans and fruit flies Drosophila melanogaster) and embryonic stages of small vertebrates such as the zebrafish Danio rerio) alongside refinement of experimental design and improved research practices to reduce the numbers of animals used and the severity of their experience. An understanding of the advantages and disadvantages of potential models is essential for researchers to determine which can best facilitate answering a specific scientific question. Applying 3Rs principles to research not only improves animal welfare but generates high-quality, reproducible and reliable data with translational relevance to human and animal patients.

Short-term impact of cardiovascular screening by traditional risk assessment or coronary artery calcium score on health-related quality of life: the ROBINSCA trial.

Aims: Evidence on the impact of screening for cardiovascular diseases (CVDs) on health-related quality of life (HRQoL) is important for policy decisions about screening implementation and to uncover teachable moments to motivate healthy lifestyle choices. It is unknown whether screening by cardiac computed tomography (CT) scan has a stronger impact on HRQoL than screening by traditional risk prediction models. The study aims to investigate differences in HRQoL across the screening process between participants who were randomized to CVD risk estimation by coronary artery calcium score or Systematic COronary Risk Evaluation. Methods and results: A subset of 2687 ROBINSCA participants filled in questionnaires at (T0) randomization, (T1) invitation, (T2) 1-3 days before screening, (T3) 1-3 days after, and (T4) screening result. Generic HRQoL (SF-12; EQ-5D) and anxiety (STAI-6) were measured. We investigated the differences in changes in HRQoL across the screening process with linear mixed models. We found comparable levels of HRQoL at all screening moments for the two intervention groups. Mental health scores were worse at invitation and randomization than at the later time points, irrespective of screening group (all P < 0.001). A result indicating a heightened CVD risk was associated with increased anxiety in the CT screening group. Conclusion: Computed tomography screening for CVD risk has no detrimental impact on HRQoL and anxiety levels compared to screening by traditional risk assessment. Receiving an invitation to screenning or a result implying increased CVD risk could function as teachable moments for high-risk individuals. Registration: ROBINSCA trial registration number: NTR6471 in Dutch Trial Register (NTR).

ANA-positive versus ANA-negative Antiphospholipid Antibody-positive Patients: Results from the APS ACTION Clinical Database and Repository.

OBJECTIVES: This study focused on the prevalence and impact of antinuclear antibodies (ANA) in antiphospholipid antibody (aPL)-positive patients without concomitant systemic autoimmune rheumatic diseases (SARDs). METHODS: Data from aPL-positive patients with or without Revised Sapporo APS classification criteria were retrieved from the APS ACTION Registry. Patients with concomitant SARDs were excluded. RESULTS: 430 aPL-positive patients were included in the analysis, 56% ANA-positive and 44% negative. ANA positivity was significantly associated with history of hematologic manifestations (persistent autoimmune hemolytic anaemia, thrombocytopenia, leukopenia and/or lymphopenia) (16% of ANA-positive vs 7% of ANA-negative, p= 0.006). Triple aPL-positivity was more frequent in the ANA-positive subgroup (p= 0.02), along with low baseline C3 and C4 levels (p= 0.05 and p= 0.009, respectively), and higher frequency for extractable nuclear antigens (ENA). Among aPL-positive patients with no APS classification, ANA-positive patients showed a higher rate of arthritis (p= 0.006). Among female patients who have experienced at least one pregnancy, 113 were ANA-positive and 96 were ANA-negative; ANA-negative patients had a higher number of pregnancies (p= 0.018), and number of live births (p= 0.014). A wider proportion of ANA-positive patients were treated with hydroxychloroquine (HCQ) (p< 0.001). CONCLUSION: When we analysed aPL-positive patients with no other SARDs, ANA status was not associated with thrombosis or pregnancy morbidity. Interestingly, ANA-positive patients showed higher rates of systemic autoimmune features, including hematologic manifestations, multiple aPL positivity, lower complement levels, ENA positivity, and joint involvement, and were more often treated with HCQ. Finally, aPL-positive subjects who were ANA-negative had a higher rate of pregnancies and live births.