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Introduction Tobacco researchers have used social media data to examine tobacco industry marketing practices (eg, influencers), and to document user experience with tobacco products. This study summarized the literature that analyzed tobacco-related social media data, including domain, social media platform, tobacco product type, and themes of findings, among other variables. Aims and Methods PubMed, PsycINFO, Web of Science, and Communication Source were searched between 2004 and 2022. Peer-reviewed articles were included if they were written in English, included at least one tobacco-related term, and one social media-related term, and analyzed a social media post. Two coders screened all-titles and abstracts. The final sample consisted of (n  = 255) articles. Studies were coded for domain, social media platform, tobacco product type, data source, type of data, coding and analytic method, and presence of validation procedure, among other variables. Results A total of 10 504 820 581 tobacco-related social media posts were assessed across 255 studies. User experience (54.1%) and promotion (23.1%) were the most researched domains. Researchers used data from Twitter the most (42.7%). Text (43.1%) was the most common type of data analyzed. Thematic analysis (80.8%) was the most common analytic technique. Themes of findings from content analyses often pertained to the health effects of tobacco use (61.0%) and promotion (44.2%). Conclusions Researchers have analyzed billions of tobacco-related social media posts to describe user experience with, and promotions related to, tobacco products like e-cigarettes on platforms like Twitter. Future research may examine tobacco-related social media data from newer platforms like TikTok. Implications Real-time surveillance of tobacco-related content on social media can keep the tobacco control community abreast of tobacco industry promotional strategies, user experience with tobacco products, and perceived health effects of tobacco use. A framework may be developed to establish best-practices for social media data collection and analysis, including strategies to identify posts from bot accounts and validate methodological approaches used in thematic analysis. [ABSTRACT FROM AUTHOR]

Psychological theory suggests that evaluators' individual values and traits play a fundamental role in evaluation practice, though few empirical studies have explored those constructs in evaluators. This paper describes an empirical study on evaluators' individual, work, and political values, as well as their personality traits to predict evaluation practice and methodological orientation. The results suggest evaluators value benevolence, achievement, and universalism; they lean socially liberal but are slightly more conservative on fiscal issues; and they tend to be conscientious, agreeable, and open to new experiences. In the workplace, evaluators value competence and opportunities for growth, as well as status and independence. These constructs did not statistically predict evaluation practice, though some workplace values and individual values predicted quantitative methodological orientation. We conclude by discussing strengths, limitations, and next steps for this line of research. [ABSTRACT FROM AUTHOR]

Abstract Tumor-associated macrophages have been well-characterized in solid malignancies, including renal cell carcinoma and generally correlate with poor prognosis. However, the molecular mechanisms which govern intratumoral macrophage behavior and patient outcome are unclear. Here, we investigated whether alterations in macrophage expression of the transcriptional regulator for myeloid commitment and function, interferon regulatory factor-8 (IRF8), could predict survival of clear cell renal cell carcinoma patients. Transcriptional analysis of publicly available data revealed elevated IRF8 expression was associated with prolonged disease-free survival. Evaluation of protein expression within histologic sections of primary clear cell renal cell carcinoma patient samples showed intensity of IRF8 by CD68+ macrophages correlated inversely with stage. Survival outcomes of patients with primary or metastatic disease could be stratified on the basis of IRF8 levels by macrophages. Patients with high levels of IRF8 expression within metastatic sites had prolonged overall survival (log-rank P

In this paper, we describe improvements to the particle swarm optimizer (PSO) made by the inclusion of an unscented Kalman filter to guide particle motion. We show how this method increases the speed of convergence, and reduces the likelihood of premature convergence, increasing the overall accuracy of optimization. We demonstrate the effectiveness of the unscented Kalman filter PSO by comparing it with the original PSO algorithm and its variants designed to improve the performance. The PSOs were tested firstly on a number of common synthetic benchmarking functions and secondly applied to a practical three-dimensional image registration problem. The proposed methods displayed better performances for 4 out of 8 benchmark functions and reduced the target registration errors by at least 2mm when registering down-sampled benchmark brain images. They also demonstrated an ability to align images featuring motion-related artifacts which all other methods failed to register. These new PSO methods provide a novel, efficient mechanism to integrate prior knowledge into each iteration of the optimization process, which can enhance the accuracy and speed of convergence in the application of medical image registration.

Neutrophils are essential to protect the host against invading pathogens but can promote disease progression in sickle cell disease (SCD) by becoming adherent to inflamed microvascular networks in peripheral tissue throughout the body. During the inflammatory response, leukocytes extravasate from the bloodstream using selectin adhesion molecules and migrate to sites of tissue insult through activation of integrins that are essential for combating pathogens. However, during vaso-occlusion associated with SCD, neutrophils are activated during tethering and rolling on selectins upregulated on activated endothelium that line blood vessels. Recently, we reported that recognition of sLex on L-selectin by E-selectin during neutrophil rolling initiates shear force resistant catch-bonds that facilitate tethering to endothelium and activation of integrin bond clusters that anchor cells to the vessel wall. Evidence indicates that blocking this important signaling cascade prevents the congestion and ischemia in microvasculature that occurs from neutrophil capture of sickled red blood cells, which are normally deformable ellipses that flow easily through small blood vessels. Two recently completed clinical trials of therapies targeting selectins and their effect on neutrophil activation in small blood vessels reveal the importance of mechanoregulation that in health is an immune adaption facilitating rapid and proportional leukocyte adhesion, while sustaining tissue perfusion. We provide a timely perspective on the mechanism underlying vaso-occlusive crisis (VOC) with a focus on new drugs that target selectin mediated integrin adhesive bond formation.

Translation-dependent quality control pathways such as no-go decay (NGD), non-stop decay (NSD), and nonsense-mediated decay (NMD) govern protein synthesis and proteostasis by resolving non-translating ribosomes and preventing the production of potentially toxic peptides derived from faulty and aberrant mRNAs. However, how translation is altered and the in vivo defects that arise in the absence of these pathways are poorly understood. Here, we show that the NGD/NSD factors Pelo and Hbs1l are critical in mice for cerebellar neurogenesis but expendable for survival of these neurons after development. Analysis of mutant mouse embryonic fibroblasts revealed translational pauses, alteration of signaling pathways, and translational reprogramming. Similar effects on signaling pathways, including mTOR activation, the translatome and mouse cerebellar development were observed upon deletion of the NMD factor Upf2. Our data reveal that these quality control pathways that function to mitigate errors at distinct steps in translation can evoke similar cellular responses.

The purpose of this study was to use item response theory to assess a brief measure of problematic smartphone use among high school students, using the 2017-18 California Student Tobacco Survey (CSTS) collected from 119,981 students who own a smartphone across 256 high schools in California. An exploratory factor analysis supported two factors that represented problematic smartphone use and concurrent behavioral issues, explaining 47% of the variance. Item response modeling demonstrated good item discrimination for problematic smartphone use (a > 1.15) and valuable test information for respondents within two standard deviations of the sample mean. Students who reported a score of 3 (somewhat agree) or 4 (agree) on each problematic smartphone use item accounted for 22% (n ​= ​25,997) of the student population who owned smartphones in our sample. Concurrent and criterion validity were found as problematic smartphone use significantly predicted smartphone use instead of sleep (b ​= ​0.35, 95% CI [0.34, 0.36], p ​

Educational success is associated with greater quality of life and depends, in part, on heritable cognitive and non-cognitive traits. We used polygenic scores (PGS) for smoking and educational attainment to examine different genetic influences on facets of academic adjustment in adolescence and educational attainment in adulthood. PGSs were calculated for participants of the Minnesota Twin Family Study (N = 3225) and included as predictors of grades, academic motivation, and discipline problems at ages 11, 14, and 17 years-old, cigarettes per day from ages 14 to 24 years old, and educational attainment in adulthood (mean age 29.4 years). Smoking and educational attainment PGSs had significant incremental associations with each academic variable and cigarettes per day. About half of the adjusted effects of the smoking and education PGSs on educational attainment in adulthood were mediated by the academic variables in adolescence. Cigarettes per day from ages 14 to 24 years old did not account for the effect of the smoking PGS on educational attainment, suggesting the smoking PGS indexes genetic influences related to general behavioral disinhibition. In sum, distinct genetic influences measured by the smoking and educational attainment PGSs contribute to academic adjustment in adolescence and educational attainment in adulthood.

Superparamagnetic iron oxide nanoparticles (SPION) are employed as diagnostics and therapeutics following intravenous delivery for the treatment of iron deficiency anemia (IDA) in adult patients with chronic kidney failure. Neutrophils are the first defense against blood borne foreign insult and recruit to vascular sites of inflammation via a sequential process that is characterized by adhesive capture, rolling, and shear resistant arrest. A primary chemotactic agonist presented on the glycocalyx of inflamed endothelium is IL-8, which upon binding to its cognate membrane receptor (CXCR1/2) activates a suite of responses in neutrophils. An early response is degranulation with accompanying upregulation of β2-integrin (CD11/CD18) and shedding of L-selectin (CD62L) receptors, which exert differential effects on the efficiency of endothelial recruitment. Feraheme is an FDA approved SPION treatment for IDA, but its effect on the innate immune response of neutrophils during inflammation has not been reported. Here, we studied the immunomodulatory effects of Feraheme on neutrophils freshly isolated from healthy human subjects and stimulated in suspension or on inflammatory mimetic substrates with IL-8. Cells treated with Feraheme exhibited reduced sensitivity to stimulation with IL-8, indicated by reduced upregulation of membrane CD11b/CD18 receptors, high affinity (HA) CD18, and shedding of CD62L. Feraheme also inhibited N-formyl-Met-Leu-Phe (fMLP) induced reactive oxygen species production. Neutrophil rolling, arrest, and migration was assessed in vascular mimetic microfluidic channels coated with E-selectin and ICAM-1 to simulate inflamed endothelium. Neutrophils exposed to Feraheme rolled faster on E-selectin and arrested less frequently on ICAM-1, in a manner dependent upon SPION concentration. Subsequent neutrophil shape change, and migration were also significantly inhibited in the presence of Feraheme. Lastly, Feraheme accelerated clearance of cytosolic calcium flux following IL-8 stimulation. We conclude that uptake of Feraheme by neutrophils inhibits chemotactic activation and downregulates normal rolling to arrest under shear flow. The mechanism involves increased calcium clearance following chemotactic activation, which may diminish the efficiency of recruitment from the circulation at vascular sites of inflammation.

Monocyte recruitment to inflamed arterial endothelium initiates plaque formation and drives progression of atherosclerosis. Three distinct monocyte subsets are detected in circulation (CD14(++)CD16(-), CD14(++)CD16(+), and CD14(+)CD16(++)), and each may play distinct roles during atherogenesis and myocardial infarction. We studied a range of subjects that included otherwise healthy patients with elevated serum triglyceride levels to patients presenting with acute myocardial infarction. Our objective was to correlate an individual's risk with the activation state of each monocyte subset as a function of changes in adhesion receptor expression using flow cytometric quantitation of integrins and l-selectin membrane expression. A microfluidic-based laboratory-on-a-chip was developed to quantify the adhesion efficiency of monocytes sheared in whole blood on vascular cell adhesion molecule-1, while characterizing adhesion receptor expression and topography on captured monocytes. CD14(++)CD16(+) monocytes adhered with sevenfold higher efficiency than other subsets, and in patients with myocardial infarction the capture efficiency of this subset was double that for healthy subjects. In patients with hypertriglyceridemia, this increase in monocyte adhesion was attributable to CD14(++)CD16(+) uptake of triglyceride-rich lipoproteins and subsequent signaling via a Phospholipase C-dependent mechanism to increase CD11c expression, very late antigen-4 function, and integrin coclustering within focal adhesive sites on vascular cell adhesion molecule-1. In summary, we introduce a unique laboratory-on-a-chip method for quantifying the activation state of monocyte subsets. These experiments reveal that CD11c/CD18 is an inducible integrin whose expression correlates with a monocyte inflammatory state in subjects at risk for atherogenesis and in patients with myocardial infarction.

Circulating triglyceride-rich lipoproteins (TGRL) from hypertriglyceridemic subjects exacerbate endothelial inflammation and promote monocyte infiltration into the arterial wall. We have recently reported that TGRL isolated from human blood after a high-fat meal can elicit a pro- or anti-atherogenic state in human aortic endothelial cells (HAEC), defined as up- or down-regulation of VCAM-1 expression in response to tumor necrosis factor alpha (TNFα) stimulation, respectively. A direct correlation was found between subjects categorized at higher risk for cardiovascular disease based upon serum triglycerides and postprandial production of TGRL particles that increased VCAM-1-dependent monocyte adhesion to inflamed endothelium. To establish how TGRL metabolism is linked to VCAM-1 regulation, we examined endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) pathways. Regardless of its atherogenicity, the rate and extent of TGRL internalization and lipid droplet formation by HAEC were uniform. However, pro-atherogenic TGRL exacerbated ER membrane expansion and stress following TNFα stimulation, whereas anti-atherogenic TGRL ameliorated such effects. Inhibition of ER stress with a chemical chaperone 4-phenylbutyric acid decreased TNFα-induced VCAM-1 expression and abrogated TGRL's atherogenic effect. Activation of ER stress sensors PKR-like ER-regulated kinase (PERK) and inositol requiring protein 1α (IRE1α), and downstream effectors including eukaryotic initiation factor-2α (eIF2α), spliced X-box-binding protein 1 (sXBP1) and C/EBP homologous protein (CHOP), directly correlated with the atherogenic activity of an individual's TGRL. Modulation of ER stress sensors also correlated with changes in expression of interferon regulatory factor 1 (IRF-1), a transcription factor of Vcam-1 responsible for regulation of its expression. Moreover, knockdown studies using siRNA defined a causal relationship between the PERK/eIF2α/CHOP pathway and IRF-1-mediated VCAM-1 expression. We conclude that ER stress and the UPR contribute to the regulation of Vcam-1 transcription as a function of the atherogenic nature of TGRL.

Despite breakthroughs in immune checkpoint inhibitor (ICI) immunotherapy, not all human cancers respond to ICI immunotherapy and a large fraction of patients with the responsive types of cancers do not respond to current ICI immunotherapy. This clinical conundrum suggests that additional immune checkpoints exist. We report here that interferon regulatory factor 8 (IRF8) deficiency led to impairment of cytotoxic T lymphocyte (CTL) activation and allograft tumor tolerance. However, analysis of chimera mice with competitive reconstitution of WT and IRF8-KO bone marrow cells as well as mice with IRF8 deficiency only in T cells indicated that IRF8 plays no intrinsic role in CTL activation. Instead, IRF8 functioned as a repressor of osteopontin (OPN), the physiological ligand for CD44 on T cells, in [CD11b.sup.+][Ly6C.sup.lo] [Ly6G.sup.+] myeloid cells and OPN acted as a potent T cell suppressor. IRF8 bound to the Spp1 promoter to repress OPN expression in colon epithelial cells, and colon carcinoma exhibited decreased IRF8 and increased OPN expression. The elevated expression of OPN in human colon carcinoma was correlated with decreased patient survival. Our data indicate that myeloid and tumor cell-expressed OPN acts as an immune checkpoint to suppress T cell activation and confer host tumor immune tolerance., Introduction[CD8.sup.+] cytotoxic T lymphocytes (CTLs) are the central component of the host adaptive immune system. A typical [CD8.sup.+] T cell immune response starts from T cell receptor (TCR) recognition of [...]

Recent research has shed light on novel functions of hematopoietic stem and progenitor cells (HSPC). While they are critical for maintenance and replenishment of blood cells in the bone marrow, these cells are not limited to the bone marrow compartment and function beyond their role in hematopoiesis. HSPC can leave bone marrow and circulate in peripheral blood and lymph, a process often manipulated therapeutically for the purpose of transplantation. Additionally, these cells preferentially home to extramedullary sites of inflammation where they can differentiate to more mature effector cells. HSPC are susceptible to various pathogens, though they may participate in the innate immune response without being directly infected. They express pattern recognition receptors for detection of endogenous and exogenous danger-associated molecular patterns and respond not only by the formation of daughter cells but can themselves secrete powerful cytokines. This paper summarizes the functional and phenotypic characterization of HSPC, their niche within and outside of the bone marrow, and what is known regarding their role in the innate immune response.

Ribosome-associated quality control pathways respond to defects in translational elongation to recycle arrested ribosomes and degrade aberrant polypeptides and mRNAs. Loss of a tRNA gene leads to ribosomal pausing that is resolved by the translational GTPase GTPBP2, and in its absence causes neuron death. Here, we show that loss of the homologous protein GTPBP1 during tRNA deficiency in the mouse brain also leads to codon-specific ribosome pausing and neurodegeneration, suggesting that these non-redundant GTPases function in the same pathway to mitigate ribosome pausing. As observed in Gtpbp2-/- mice (Ishimura et al., 2016), GCN2-mediated activation of the integrated stress response (ISR) was apparent in the Gtpbp1-/- brain. We observed decreased mTORC1 signaling which increased neuronal death, whereas ISR activation was neuroprotective. Our data demonstrate that GTPBP1 functions as an important quality control mechanism during translation elongation and suggest that translational signaling pathways intricately interact to regulate neuronal homeostasis during defective elongation.

The immune system plays a critical role in cancer progression and response to therapy. However, the immune system can be compromised during the neoplastic process. Notably, the myeloid lineage, which gives rise to granulocytic cells, including neutrophils, is a well-recognized target of tumor-mediated immune suppression. Ordinarily, granulocytic cells are integral for host defense, but in neoplasia the normal process of granulocyte differentiation (i.e., granulopoiesis) can be impaired leading instead to the formation of granulocytic (or PMN)-myeloid-derived suppressor cells (MDSCs). Such cells comprise various stages of myeloid differentiation and are defined functionally by their highly pro-tumorigenic and immune suppressive activities. Thus, considerable interest has been devoted to impeding the negative contributions of PMN-MDSCs to the antitumor response. Understanding their biology has the potential to unveil novel therapeutic opportunities to hamper PMN-MDSC production in the bone marrow, their mobilization, or their effector functions within the tumor microenvironment and, therefore, bolster anticancer therapies that require a competent myeloid compartment. In this review, we will highlight mechanisms by which the neoplastic process skews granulopoiesis to produce PMN-MDSCs, summarize mechanisms by which they execute their pro-tumorigenic activities and, lastly, underscore strategies to obstruct their role as negative regulators of antitumor immunity.

Introduction: The purpose of this report is to describe barriers and solutions to the implementation and optimization of a pragmatic trial that tests an evidence-based, patient-centered, low literacy intervention promoting diabetes self-care in rural primary care clinics. Methods: The two-arm pragmatic trial has been implemented in six rural family medicine clinics in Arkansas. It tests a self-management education and counseling intervention for patients with type 2 diabetes compared to enhanced usual care. Barriers and solutions were identified as issues arose and through interviews with clinic directors and clinic administrators and a focus group, interviews, and tracking reports with clinic health coaches who delivered the intervention. Results: Barriers to optimizing enrollment, intervention delivery, and data collection were addressed through targeted education of and relationship building with leadership, changing enrollment oversight, and ongoing training of health coaches. Conclusions: Successful implementation and optimization of this pragmatic clinical trial in rural primary care clinics was achieved through establishing common goals with clinic leadership, minimizing demands on clinic staff and administration, frequent contact and ongoing support of health coaches, and collaborative troubleshooting of issues with delivering the intervention.

Outbreaks of emerging coronaviruses in the past two decades and the current pandemic of a novel coronavirus (SARS-CoV-2) that emerged in China highlight the importance of this viral family as a zoonotic public health threat. To gain a better understanding of coronavirus presence and diversity in wildlife at wildlife-human interfaces in three southern provinces in Viet Nam 2013-2014, we used consensus Polymerase Chain Reactions to detect coronavirus sequences. In comparison to previous studies, we observed high proportions of positive samples among field rats (34.0%, 239/702) destined for human consumption and insectivorous bats in guano farms (74.8%, 234/313) adjacent to human dwellings. Most notably among field rats, the odds of coronavirus RNA detection significantly increased along the supply chain from field rats sold by traders (reference group; 20.7% positivity, 39/188) by a factor of 2.2 for field rats sold in large markets (32.0%, 116/363) and 10.0 for field rats sold and served in restaurants (55.6%, 84/151). Coronaviruses were also detected in rodents on the majority of wildlife farms sampled (60.7%, 17/28). These coronaviruses were found in the Malayan porcupines (6.0%, 20/331) and bamboo rats (6.3%, 6/96) that are raised on wildlife farms for human consumption as food. We identified six known coronaviruses in bats and rodents, clustered in three Coronaviridae genera, including the Alpha-, Beta-, and Gammacoronaviruses. Our analysis also suggested either mixing of animal excreta in the environment or interspecies transmission of coronaviruses, as both bat and avian coronaviruses were detected in rodent feces on wildlife farms. The mixing of multiple coronaviruses, and their apparent amplification along the wildlife supply chain into restaurants, suggests maximal risk for end consumers and likely underpins the mechanisms of zoonotic spillover to people.

Abstract Background Amphiregulin (AREG), a ligand of the epidermal growth factor receptor, is not only essential for proper mammary ductal development, but also associated with breast cancer proliferation and growth. In the absence of AREG, mammary ductal growth is stunted and fails to expand. Furthermore, suppression of AREG expression in estrogen receptor-positive breast tumor cells inhibits in-vitro and in-vivo growth. Methods We crossed AREG-null (AREG−/−) mice with the murine luminal B breast cancer model, MMTV-PyMT (PyMT), to generate spontaneous breast tumors that lack AREG (AREG−/− PyMT). We evaluated tumor growth, cytokeratin-8 (K8)-positive luminal cells, cytokeratin-14 (K14)-positive myoepithelial cells, and expression of AREG, Ki67, and PyMT. Primary myoepithelial cells from nontumor-bearing AREG+/+ mice underwent fluorescence-activated cell sorting and were adapted to culture for in-vitro coculture studies with AT-3 cells, a cell line derived from C57Bl/6 PyMT mammary tumors. Results Intriguingly, PyMT-induced lesions progress more rapidly in AREG−/− mice than in AREG+/+ mice. Quantification of K8+ luminal and K14+ myoepithelial cells in non-PyMT AREG−/− mammary glands showed fewer K14+ cells and a thinner myoepithelial layer. Study of AT-3 cells indicated that coculture with myoepithelial cells or exposure to AREG, epidermal growth factor, or basic fibroblast growth factor can suppress PyMT expression. Late-stage AREG−/− PyMT tumors are significantly less solid in structure, with more areas of papillary and cystic growth. Papillary areas appear to be both less proliferative and less necrotic. In The Cancer Genome Atlas database, luminal-B invasive papillary carcinomas have lower AREG expression than luminal B invasive ductal carcinomas. Conclusions Our study has revealed a previously unknown role of AREG in myoepithelial cell development and PyMT expression. AREG expression is essential for proper myoepithelial coverage of mammary ducts. Both AREG and myoepithelial cells can suppress PyMT expression. We find that lower AREG expression is associated with invasive papillary breast cancer in both the MMTV-PyMT model and human breast cancer.

Abstract Background Accurate assessment of liver health prior to undertaking resectional liver surgery or chemoembolisation for primary and secondary cancers is essential for patient safety and optimal outcomes. LiverMultiScan™, an MRI-based technology, non-invasively quantifies hepatic fibroinflammatory disease, steatosis and iron content. We hypothesise that LiverMultiScan™can quantify liver health prior to surgery and inform the risk assessment for patients considering liver surgery or chemoembolization and seek to evaluate this technology in an operational environment. Methods/Design HepaT1ca is an observational cohort study in two tertiary-referral liver surgery centres in the United Kingdom. The primary outcome is correlation between the pre-operative liver health assessment score (Hepatica score - calculated by weighting future remnant liver volume by liver inflammation and fibrosis (LIF) score) and the post-operative liver function composite integer-based risk (Hyder-Pawlik) score. With ethical approval and fully-informed consent, individuals considering liver surgery for primary or secondary cancer will undergo clinical assessment, blood sampling, and LiverMultiScan™multiparametric MRI before and after surgical liver resection or TACE. In nested cohorts of individuals undergoing chemotherapy prior to surgery, or those undergoing portal vein embolization (PVE) as an adjunct to surgery, an additional testing session prior to commencement of treatment will occur. Tissue will be examined histologically and by immunohistochemistry. Pre-operative liver health assessment scores and the post-operative risk scores will be correlated to define the ability of LiverMultiScan™to predict the risk of post-operative morbidity and mortality. Because technology performance in this setting is unknown, a pragmatic sample size will be used. For the primary outcome, n = 200 for the main cohort will allow detection of a minimum correlation coefficient of 0.2 with 5% significance and power of 80%. Discussion This study will refine the technology and clinical application of multiparametric MRI (including LiverMultiScan™), to quantify pre-existing liver health and predict post-intervention outcomes following liver resection. If successful, this study will advance the technology and support the use of multiparametric MRI as part of an enhanced pre-operative assessment to improve patient safety and to personalise operative risk assessment of liver surgery/non-surgical intervention. Trial registration This study is registered on ClinicalTrials.gov Identifier: NCT03213314.

BackgroundPost-arthroplasty infections represent a devastating complication of total joint replacement surgery, resulting in multiple reoperations, prolonged antibiotic use, extended disability and worse clinical outcomes. As the number of arthroplasties in the U.S. will exceed 3.8 million surgeries per year by 2030, the number of post-arthroplasty infections is projected to increase to over 266,000 infections annually. The treatment of these infections will exhaust healthcare resources and dramatically increase medical costs.Methodology/principal findingsTo evaluate novel preventative therapeutic strategies against post-arthroplasty infections, a mouse model was developed in which a bioluminescent Staphylococcus aureus strain was inoculated into a knee joint containing an orthopaedic implant and advanced in vivo imaging was used to measure the bacterial burden in real-time. Mice inoculated with 5x10(3) and 5x10(4) CFUs developed increased bacterial counts with marked swelling of the affected leg, consistent with an acute joint infection. In contrast, mice inoculated with 5x10(2) CFUs developed a low-grade infection, resembling a more chronic infection. Ex vivo bacterial counts highly correlated with in vivo bioluminescence signals and EGFP-neutrophil fluorescence of LysEGFP mice was used to measure the infection-induced inflammation. Furthermore, biofilm formation on the implants was visualized at 7 and 14 postoperative days by variable-pressure scanning electron microscopy (VP-SEM). Using this model, a minocycline/rifampin-impregnated bioresorbable polymer implant coating was effective in reducing the infection, decreasing inflammation and preventing biofilm formation.Conclusions/significanceTaken together, this mouse model may represent an alternative pre-clinical screening tool to evaluate novel in vivo therapeutic strategies before studies in larger animals and in human subjects. Furthermore, the antibiotic-polymer implant coating evaluated in this study was clinically effective, suggesting the potential for this strategy as a therapeutic intervention to combat post-arthroplasty infections.

Platelet transmission electron microscopy (PTEM) is considered the gold standard test for assessing distinct ultrastructural abnormalities in inherited platelet disorders (IPDs). Nevertheless, PTEM remains mainly a research tool due to the lack of standardized procedures, a validated dense granule (DG) count reference range, and standardized image interpretation criteria. The aim of this study was to standardize and validate PTEM as a clinical laboratory test. Based on previously established methods, we optimized and standardized preanalytical, analytical, and postanalytical procedures for both whole mount (WM) and thin section (TS) PTEM. Mean number of DG/platelet (plt), percentage of plts without DG, platelet count (PC), mean platelet volume (MPV), immature platelet fraction (IPF), and plt light transmission aggregometry analyses were measured on blood samples from 113 healthy donors. Quantile regression was used to estimate the reference range for DG/plt, and linear regression was used to assess the association of DG/plt with other plt measurements. All PTEM procedures were standardized using commercially available materials and reagents. DG interpretation criteria were established based on previous publications and expert consensus, and resulted in improved operator agreement. Mean DG/plt was stable for 2 days after blood sample collection. The median within patient coefficient of variation for mean DG/plt was 22.2%; the mean DG/plt reference range (mid-95th %) was 1.2–4.0. Mean DG/plt was associated with IPF (p = .01, R2 = 0.06) but not age, sex, PC, MPV, or plt maximum aggregation or primary slope of aggregation (p > .17, R2

Abstract Understanding the functional impact of genomic variants is a major goal of modern genetics and personalized medicine. Although many synonymous and non-coding variants act through altering the efficiency of pre-mRNA splicing, it is difficult to predict how these variants impact pre-mRNA splicing. Here, we describe a massively parallel approach we use to test the impact on pre-mRNA splicing of 2059 human genetic variants spanning 110 alternative exons. This method, called variant exon sequencing (Vex-seq), yields data that reinforce known mechanisms of pre-mRNA splicing, identifies variants that impact pre-mRNA splicing, and will be useful for increasing our understanding of genome function.