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Abstract Alteration of basaltic glass and in situ mineral growth are fundamental processes that influence the chemical and material properties of Earth’s oceanic crust. These processes have evolved at the basaltic island of Surtsey (SW Iceland) since eruptions terminated in 1967. Here, subaerial and submarine lapilli tuff samples from a 192 m-deep borehole drilled in 2017 (SE-02b) are characterized through petrographic studies, X-ray powder diffraction analyses, and SEM–EDS imaging and chemical analyses. The integrated results reveal (i) multi-stage palagonitization processes in basaltic glass and precipitation of secondary minerals from matrix pore fluids, (ii) multi-stage crystallization of secondary phillipsite, analcime and Al-tobermorite in the vesicles of basaltic pyroclasts and (iii) variations in palagonitization processes as a function of thermal and hydrological domains. Although temperature appears to be an important factor in controlling rates of secondary mineralization, the chemistry of original basaltic components and interstitial fluids also influences reaction pathways in the young pyroclastic deposits. The integration of systematic mineralogical analyses of the 50-year-old tuff from one of the most carefully monitored volcanic sites on Earth, together with temperature monitoring in boreholes since 1980, provide a reference framework for evaluating mineralogical evolution in other Surtseyan-type volcanoes worldwide.

Background: Heart murmurs in puppies can be innocent or pathologic; the latter is almost always related to a congenital heart disease. Differentiating between these murmurs can be challenging for practicing veterinarians, but this differentiation is essential to ensure the best prognosis for puppies having a congenital heart disease. Our study aimed to reveal how veterinarians manage puppies with a heart murmur. Methods: A web-based questionnaire was sent to Dutch and Belgian veterinary practices. Results: Data from 452 respondents were analyzed. Though 88% of the respondents find detecting a heart murmur easy, only 9% find differentiating innocent murmurs from pathologic murmurs in puppies easy. Of the respondents, only 80% recommend immediate additional examination when detecting a loud heart murmur during the first veterinary health check at 6 weeks of age. Most of the respondents are aware that normal growth and the absence of clinical signs do not exclude severe congenital heart disease. Of the respondents, 31% were uncertain whether early surgical intervention could lead to improved outcomes. Conclusions: Veterinarians are aware of the importance of echocardiography for puppies with a loud heart murmur, and recognize their limitations when differentiating an innocent from a pathological heart murmur in a puppy.

Abstract Background The underlying motivation of this work is to demonstrate that artificial muscle activity of known and unknown motion can be generated based on motion parameters, such as angular position, acceleration, and velocity of each joint (or the end-effector instead), which are similarly represented in our brains. This model is motivated by the known motion planning process in the central nervous system. That process incorporates the current body state from sensory systems and previous experiences, which might be represented as pre-learned inverse dynamics that generate associated muscle activity. Methods We develop a novel approach utilizing recurrent neural networks that are able to predict muscle activity of the upper limbs associated with complex 3D human arm motions. Therefore, motion parameters such as joint angle, velocity, acceleration, hand position, and orientation, serve as input for the models. In addition, these models are trained on multiple subjects (n=5 including , 3 male in the age of 26±2 years) and thus can generalize across individuals. In particular, we distinguish between a general model that has been trained on several subjects, a subject-specific model, and a specific fine-tuned model using a transfer learning approach to adapt the model to a new subject. Estimators such as mean square error MSE, correlation coefficient r, and coefficient of determination R 2 are used to evaluate the goodness of fit. We additionally assess performance by developing a new score called the zero-line score. The present approach was compared with multiple other architectures. Results The presented approach predicts the muscle activity for previously through different subjects with remarkable high precision and generalizing nicely for new motions that have not been trained before. In an exhausting comparison, our recurrent network outperformed all other architectures. In addition, the high inter-subject variation of the recorded muscle activity was successfully handled using a transfer learning approach, resulting in a good fit for the muscle activity for a new subject. Conclusions The ability of this approach to efficiently predict muscle activity contributes to the fundamental understanding of motion control. Furthermore, this approach has great potential for use in rehabilitation contexts, both as a therapeutic approach and as an assistive device. The predicted muscle activity can be utilized to guide functional electrical stimulation, allowing specific muscles to be targeted and potentially improving overall rehabilitation outcomes.

Background: Myxomatous mitral valve degeneration is the most common canine heart disease. Several clinical trials have investigated various treatments. The latest recommendations are published in the ACVIM consensus guidelines (2019). Our study aimed to investigate how closely veterinary practitioners apply the treatment recommendations of these guidelines and the latest clinical trials. Methods: An online survey was sent to Dutch and Belgian veterinary practices via digital channels. Results: The data from 363 fully completed surveys were analyzed. For stage B1 disease, 93% recommended, correctly, no treatment. For stage B2 disease, 67% of the respondents recommended starting pimobendan as monotherapy. For chronic treatment of stage C disease, 16 different drug combinations were mentioned, but nobody recommended surgery. Only 48% of the respondents recommended the only evidence-based drug combination: a loop diuretic with pimobendan. A concerning finding was the simultaneous prescription of two loop diuretics, by 19% of the respondents. Conclusions: Treatment recommendations showed an increasing variation with more advanced disease stages from B1 through B2 to C. This reflects the increasing disagreement among the panelists who prepared the ACVIM consensus guidelines. Practitioners of our study seem to practice more evidence-based medicine than veterinary cardiologists, as it was reported in a recent survey-based study.

Background: ACVIM developed and published guidelines for staging myxomatous mitral valve degeneration in dogs in 2009. An updated version was published in 2019. The present study aimed to investigate whether these guidelines are actually used by the intended public more than a decade after their first publication. Methods: An online survey was distributed among Dutch and Belgian veterinarians through online channels and mailing lists. Results: Of the 524 responses, only 363 complete surveys were analyzed. The ACVIM guidelines are used by 60% of the respondents. Veterinarians find it more difficult to differentiate stage B1 from B2 in asymptomatic dogs compared to diagnosing stage C. Three-quarters of the respondents would recommend echocardiography for an incidentally detected new murmur with an intensity of 3 out of 6 in an adult dog. Two-thirds of the respondents find coughing a convincing finding for stage C disease. Close to half of the respondents associate a horizontal, dull percussion line with pulmonary edema. For confirming cardiogenic pulmonary edema, 98% of the respondents used thoracic radiographs. Conclusions: Veterinary practitioners might not have the expected training and equipment to be able to apply the guidelines in their practices, especially in the differentiation of stage B1 from stage B2.

BACKGROUND Fibrocytes are BM-derived circulating cells that traffic to the injured lungs and contribute to fibrogenesis. The mTOR inhibitor, sirolimus, inhibits fibrocyte CXCR4 expression, reducing fibrocyte traffic and attenuating lung fibrosis in animal models. We sought to test the hypothesis that short-term treatment with sirolimus reduces the concentration of CXCR4+ circulating fibrocytes in patients with idiopathic pulmonary fibrosis (IPF).METHODS We conducted a short-term randomized double-blind placebo-controlled crossover pilot trial to assess the safety and tolerability of sirolimus in IPF. Participants were randomly assigned to sirolimus or placebo for approximately 6 weeks, and after a 4-week washout, they were assigned to the alternate treatment. Toxicity, lung function, and the concentration of circulating fibrocytes were measured before and after each treatment.RESULTS In the 28 study participants, sirolimus resulted in a statistically significant 35% decline in the concentration of total fibrocytes, 34% decline in CXCR4+ fibrocytes, and 42% decline in fibrocytes expressing α-smooth muscle actin, but no significant change in these populations occurred on placebo. Respiratory adverse events occurred more frequently during treatment with placebo than sirolimus; the incidence of adverse events and drug tolerability did not otherwise differ during therapy with drug and placebo. Lung function was unaffected by either treatment, with the exception of a small decline in gas transfer during treatment with placebo.CONCLUSION As compared with placebo, short-term treatment with sirolimus resulted in reduction of circulating fibrocyte concentrations in participants with IPF, with an acceptable safety profile.TRIAL REGISTRATION ClinicalTrials.gov, accession no. NCT01462006.FUNDING NIH R01HL098329 and American Heart Association 18TPA34170486.

Abstract Background Autophagy plays an essential role in maintaining cellular homeostasis and in the response to cellular stress. Autophagy is also involved in cell cycle progression, yet the relationship between these processes is not clearly defined. Results In exploring this relationship, we observed that the inhibition of autophagy impaired the G2/M phase-arresting activity of etoposide but enhanced the G1 phase-arresting activity of palbociclib. We further investigated the connection of basal autophagy and cell cycle by utilizing the autophagosome tracer dye Cyto-ID in two ways. First, we established a double-labeling flow-cytometric procedure with Cyto-ID and the DNA probe DRAQ5, permitting the cell cycle phase-specific determination of autophagy in live cells. This approach demonstrated that different cell cycle phases were associated with different autophagy levels: G1-phase cells had the lowest level, and G2/M-phase cells had the highest one. Second, we developed a flow-cytometric cell-sorting procedure based on Cyto-ID that separates cell populations into fractions with low, medium, and high autophagy. Cell cycle analysis of Cyto-ID-sorted cells confirmed that the high-autophagy fraction contained a much higher percentage of G2/M-phase cells than the low-autophagy fraction. In addition, Cyto-ID-based cell sorting also proved to be useful for assessing other autophagy-related processes: extracellular flux analysis revealed metabolic differences between the cell populations, with higher autophagy being associated with higher respiration, higher mitochondrial ATP production, and higher glycolysis. Conclusion This work provides clear evidence of high autophagy in G2/M-phase cells by establishing a novel cell sorting technique based on Cyto-ID.

BackgroundElectronic health records (EHRs) have the potential to facilitate consistent clinical data capture to support excellence in patient care, quality improvement, and knowledge generation. Despite widespread EHR use, the vision to transform health care system and its data to a "learning health care system" generating knowledge from real-world data is limited by the lack of consistent, structured clinical data. ObjectiveThe purpose of this paper was to demonstrate the design of a web-based structured clinical intervention data capture system and its evaluation in practice. The use case was ambulatory physical therapy (PT) treatment after total knee replacement (TKR), one of the most common and costly procedures today. MethodsTo identify the PT intervention type and intensity (or dose) used to treat patients with knee arthritis following TKR, an iterative user-centered design process refined an initial list of PT interventions generated during preliminary chart reviews. Input from practicing physical therapists and national and international experts refined and categorized the interventions. Next, a web-based, hierarchical structured system for intervention and intensity documentation was designed and deployed. ResultsThe PT documentation system was implemented by 114 physical therapists agreeing to record all interventions at patient visits. Data for 161 patients with 2615 PT visits were entered by 83 physical therapists. No technical problems with data entry were reported, and data entry required less than 2 minutes per visit. A total of 42 (2%) interventions could not be categorized and were recorded using free text. ConclusionsThe use of user-centered design principles provides a road map for developing clinically feasible data capture systems that employ structured collection of uniform data for use by multiple practitioners across institutions to complement and augment existing EHRs. Secondarily, these data can be analyzed to define best practices and disseminate knowledge to practice.

Background: A high perinatal mortality rate in the Stabyhoun breed prompted one of the Dutch breeding organizations to start an investigation. Preductal segmental tubular aortic hypoplasia is an extremely rarely documented congenital vascular anomaly in dogs, and it is suspected to be the result of constriction of ectopic ductal tissue in the aortic wall at birth. Methods: Over a period of 18 months, Stabyhoun puppies that were stillborn, died or were euthanized before 3 weeks of age were submitted to post-mortem examination at the reporting institution. Pathologic findings were documented. Results: Eight Stabyhoun puppies were submitted during the study period. In five of them, a severe preductal segmental tubular aortic hypoplasia was found. Two of the five puppies were stillborn, and three died spontaneously or were euthanized. Conclusions: Preductal tubular aortic hypoplasia was found in an unusually high frequency in the examined Stabyhoun puppies. Because the condition is believed to cause clinical signs only after birth, this anomaly cannot explain the death of the stillborn puppies. However, it might be responsible for cardiogenic pulmonary edema in the postnatal period. Routine dissection of the great vessels in perinatally deceased puppies would help to establish the prevalence of congenital anomalies of the aorta.

Abstract Background Fibrosis is an integral component of the pathogenesis of acute lung injury and is associated with poor outcomes in patients with acute respiratory distress syndrome (ARDS). Fibrocytes are bone marrow-derived cells that traffic to injured tissues and contribute to fibrosis; hence their concentration in the peripheral blood has the potential to serve as a biomarker of lung fibrogenesis. We therefore sought to test the hypothesis that the concentration and phenotype of circulating fibrocytes in patients with ARDS predicts clinical outcomes. Methods For the animal studies, C57Bl/6 mice were infected with experimental Klebsiella pneumoniae in a model of acute lung injury; one-way ANOVA was used to compare multiple groups and two-way ANOVA was used to compare two groups over time. For the human study, 42 subjects with ARDS and 12 subjects with pneumonia (without ARDS) were compared to healthy controls. Chi-squared or Fisher’s exact test were used to compare binary outcomes. Survival data was expressed using a Kaplan-Meier curve and compared by log-rank test. Univariable and multivariable logistic regression were used to predict death. Results In mice with acute lung injury caused by Klebsiella pneumonia, there was a time-dependent increase in lung soluble collagen that correlated with sequential expansion of fibrocytes in the bone marrow, blood, and then lung compartments. Correspondingly, when compared via cross-sectional analysis, the initial concentration of blood fibrocytes was elevated in human subjects with ARDS or pneumonia as compared to healthy controls. In addition, fibrocytes from subjects with ARDS displayed an activated phenotype and on serial measurements, exhibited intermittent episodes of markedly elevated concentration over a median of 1 week. A peak concentration of circulating fibrocytes above a threshold of > 4.8 × 106 cells/mL cells correlated with mortality that was independent of age, ratio of arterial oxygen concentration to the fraction of inspired oxygen, and vasopressor requirement. Conclusions Circulating fibrocytes increase in a murine model of acute lung injury and elevation in the number of these cells above a certain threshold is correlated with mortality in human ARDS. Therefore, these cells may provide a useful and easily measured biomarker to predict outcomes in these patients.

Study objective: Infarct size is a strong predictor of outcomes after ST elevation myocardial infarction (STEMI). Circulating fibrocytes are bone marrow-derived progenitor cells associated with fibrotic processes. We tested whether fibrocytes correlate with infarct size in STEMI patients treated with primary percutaneous coronary intervention (PCI). Design: Prospective observational study. Setting: Academic medical center. Participants: Subjects with STEMI treated with primary PCI. Interventions: Peripheral blood draw and cardiac magnetic resonance imaging (CMR). Main outcome measure: Correlation of fibrocyte levels with infarct size. Methods: Peripheral blood fibrocytes were quantified at discharge from STEMI hospitalization and at 6 months follow-up using flow cytometry. Infarct size was determined within 2 weeks of discharge and at 6 months follow-up using late gadolinium enhancement on CMR. Results: Among 14 patients (median age 54 years, 79% men) with STEMI, there was a statistically significant positive correlation between fibrocyte levels at 6 months and 6-month infarct size on CMR (r = 0.58, p = 0.031). In addition, there was positive correlation between peak troponin I level (r = 0.85, p

Abstract The p53 tumor suppressor regulates distinct responses to cellular stresses. Although different stresses generate different p53 dynamics, the mechanisms by which cells decode p53 dynamics to differentially regulate target genes are not well understood. Here, we determined in individual cells how canonical p53 target gene promoters vary in responsiveness to features of p53 dynamics. Employing a chemical perturbation approach, we independently modulated p53 pulse amplitude, duration, or frequency, and we then monitored p53 levels and target promoter activation in individual cells. We identified distinct signal processing features—thresholding in response to amplitude modulation, a refractory period in response to duration modulation, and dynamic filtering in response to frequency modulation. We then showed that the signal processing features not only affect p53 target promoter activation, they also affect p53 regulation and downstream cellular functions. Our study shows how different promoters can differentially decode features of p53 dynamics to generate distinct responses, providing insight into how perturbing p53 dynamics can be used to generate distinct cell fates.

Introduction: Total hip and total knee replacement (THR and TKR) are suggested for reducing joint pain resulting from hip and knee osteoarthritis (OA), especially when other interventions have not resulted in desired outcomes. Providing prehabilitation education can improve patients’ psychological and physical well-being before and after surgery. The use of electronic health (eHealth) tools can be considered an effective method to increase patients’ access to prehabilitation, particularly for those facing barriers to attending diagnosis-specific in-person education sessions. However, limited attention is paid to both caregiver and patient perspectives regarding the delivery formats, features, and characteristics of eHealth tools. Method: Patients with hip (n = 46) and knee OA (n = 14) and their family caregivers (n = 16) participated in in-person focus groups or phone interviews. Participants were shown a mock-up of an eHealth module, and asked to share their preferences regarding the formats, features, and characteristics of the eHealth prehabilitation tool. Data was transcribed verbatim and coded using primary thematic and secondary content analyses. Result: Analyses revealed 3 main themes: 1. “easier to understand” emphasizes patients’ preferences on delivery formats and features; 2. “what does that mean?” highlights requests for clear and simple information; and 3. “Preparation, right?” shows patients’ perspectives on the best time to have access to the eHealth tool. Discussion: Participants’ preferences for prehabilitation tools included offering eHealth tools in multiple mediums of delivery (eg, written materials, pictures, videos). Participants preferred simplified information that emphasized the key points and rationale for the knowledge. There were differences in preferred timeline for having access to prehabilitation education, such as some participants wanting to receive prehabilitation well in advance, while others stated just before surgery was adequate. Our findings provide novel and actionable information about patient and caregiver perspectives on features and characteristics of prehabilitation education for patients with hip and knee OA.

Aims: Patients undergoing aortic valve replacement (AVR) for severe aortic stenosis have a 6–16% prevalence of occult cardiac amyloidosis. Carpal tunnel syndrome (CTS) is common in cardiac amyloidosis, but whether prior CTS surgery has a prognostic impact in patients undergoing AVR is unknown. This study examined the association between prior CTS surgery and adverse cardiovascular outcomes in patients treated with AVR. Methods and results: Using Danish nationwide registries, we retrospectively identified patients undergoing first-time AVR from 2005 to 2018, examining the association between previous CTS and adverse cardiovascular outcomes the following 5 years after the AVR procedure. Cumulative incidence functions and adjusted Cox proportional hazard models were used to assess differences. Among 19,211 patients undergoing AVR, 2.5% (n = 472) had prior CTS surgery. Patients in the CTS-cohort were significantly older (median age 75.7 [IQR 68.1–82.3] vs 73.7 [IQR 66.0–79.6]), more often female and had more comorbidities. Prior CTS surgery was not associated with differences in hospitalization for heart failure (11.2% [95% CI 8.3–14.7] vs 9.4% [95% CI 9.0–9.9]), atrial fibrillation (11.1% [95% CI 8.2–14.5] vs 11.2% [95% CI 10.8–11.7]) or pacemaker implantation (6.2% [95% CI 4.0–9.0] vs 5.1% [95% CI 4.8–5.5]). The 5-year mortality (32.8% [27.6–38.0] vs 25.2% [24.5–25.9]) was higher in the CTS-cohort. CTS was significantly associated with increased 5-year mortality (HR 1.27 [1.05–1.53]) in crude models, however, after multivariable adjustment prior CTS surgery was not associated with adverse cardiovascular outcomes. Conclusion: Previous CTS surgery was not associated with increased risk for adverse cardiovascular outcomes after AVR.

Background Autoimmunity is a common cause of pulmonary fibrosis and can present either as a manifestation of an established connective tissue disease or as the recently described entity of interstitial pneumonia with autoimmune features. The rate of progression and responsiveness to immunosuppression in these illnesses are difficult to predict. Circulating fibrocytes are bone marrow-derived progenitor cells that home to injured tissues and contribute to lung fibrogenesis. We sought to test the hypothesis that the blood fibrocyte concentration predicts outcome and treatment responsiveness in autoimmune interstitial lung diseases. Methods We compared the concentration of circulating fibrocytes in 50 subjects with autoimmune interstitial lung disease and 26 matched healthy controls and assessed the relationship between serial peripheral blood fibrocyte concentrations and clinical outcomes over a median of 6.25 years. Results As compared to controls, subjects with autoimmune interstitial lung disease had higher circulating concentrations of total fibrocytes, the subset of activated fibrocytes, and fibrocytes with activation of PI3K/AKT/mTOR, transforming growth factor-β (TGF-β) receptor and interleukin (IL)-4/IL-13 receptor signalling pathways. Over the follow-up period, there were episodes of marked elevation in the concentration of circulating fibrocytes in subjects with autoimmune interstitial lung disease but not controls. Initiation of immunosuppressive therapy was associated with a decline in the concentration of circulating fibrocytes. For each 100 000 cells·mL−1 increase in peak concentration of circulating fibrocytes, we found a 5% increase in odds of death or lung function decline. Conclusion In patients with autoimmune interstitial lung disease, circulating fibrocytes may represent a biomarker of outcome and treatment response.

The induction of synaptic plasticity requires the presence of temporally patterned neural activity. Numerous cellular studies in animals and brain slices have demonstrated that long-term potentiation (LTP) enhances synaptic transmission, which can be evoked by high-frequency intermittent stimulation. In humans, plasticity processes underlying perceptual learning can be reliably induced by repetitive, LTP-like sensory stimulation. These protocols lead to improvement of perceptual abilities parallel to widespread remodeling of cortical processing. However, whether maintained rhythmic cortical activation induced by the LTP-like stimulation is also present during human perceptual learning experiments, remains elusive. To address this question, we here applied a 20 Hz intermittent stimulation protocol for 40 min to the index-, middle- and ring-fingers of the right hand, while continuously recording EEG over the hand representation in primary somatosensory cortex in young adult participants. We find that each train of stimulation initiates a transient series of sensory-evoked potentials which accumulate after about 500 ms into a 20 Hz steady-state response persisting over the entire period of the 2-s-train. During the inter-train interval, no consistent evoked activity can be detected. This response behavior is maintained over the whole 40 min of stimulation without any indication of habituation. However, the early stimulation evoked potentials (SEPs) and the event-related desynchronization (ERD) during the steady-state response change over the 40 min of stimulation. In a second experiment, we demonstrate in a separate cohort of participants that the here-applied pneumatic type of stimulation results in improvement of tactile acuity as typically observed for electrically applied 20 Hz intermittent stimulation. Our data demonstrate that repetitive stimulation using a 20 Hz protocol drives rhythmic activation in the hand representation of somatosensory cortex, which is sustained during the entire stimulation period. At the same time, cortical excitability increases as indicated by altered ERD and SEP amplitudes. Our results, together with previous data underlining the dependence of repetitive sensory stimulation effects on NMDA-receptor activation, support the view that repetitive sensory stimulation elicits LTP-like processes in the cortex, thereby facilitating perceptual learning processes.

Abstract Background To compare visual function and structural improvements in pseudophakic eyes with diabetic macular oedema (DMO) treated with the 0.19mg Fluocinolone Acetonide (FAc) intravitreal implant (IluvienTM) in a ‘real world’ setting. Methods A single centre retrospective evaluation of patients with DMO unresponsive to conventional treatment treated with the FAc implant according to UK guidelines. Primary efficacy endpoint was best corrected visual acuity (BCVA); secondary endpoints included optical coherence tomography evaluations of the macula (a) central retinal and (b) peak macular thickness collected at annual time points. Primary safety endpoint was new rise in IOP >27mmHg or glaucoma surgery. Patients with

ONC201/TIC10 is a first-in-class small molecule inducer of TRAIL that causes early activation of the integrated stress response. Its promising safety profile and broad-spectrum efficacy in vitro have been confirmed in Phase I/II trials in several advanced malignancies. Binding and reporter assays have shown that ONC201 is a selective antagonist of the dopamine D2-like receptors, specifically, DRD2 and DRD3. We hypothesized that ONC201’s interaction with DRD2 plays a role in ONC201’s anticancer effects. Using cBioportal and quantitative reverse-transcription polymerase chain reaction analyses, we confirmed that DRD2 is expressed in different cancer cell types in a cell type–specific manner. On the other hand, DRD3 was generally not detectable. Overexpressing DRD2 in cells with low DRD2 levels increased ONC201-induced PARP cleavage, which was preceded and correlated with an increase in ONC201-induced CHOP mRNA expression. On the other hand, knocking out DRD2 using CRISPR/Cas9 in three cancer cell lines was not sufficient to abrogate ONC201’s anticancer effects. Although ONC201’s anticancer activity was not dependent on DRD2 expression in the cancer cell types tested, we assessed the cytotoxic potential of DRD2 blockade. Transient DRD2 knockdown in HCT116 cells activated the integrated stress response and reduced cell number. Pharmacological antagonism of DRD2 significantly reduced cell viability. Thus, we demonstrate in this study that disrupting dopamine receptor expression and activity can have cytotoxic effects that may at least be in part due to the activation of the integrated stress response. On the other hand, ONC201’s anticancer activity goes beyond its ability to antagonize DRD2, potentially due to ONC201’s ability to activate other pathways that are independent of DRD2. Nevertheless, blocking the dopamine D1-like receptor DRD5 via siRNA or the use of a pharmacological antagonist promoted ONC201-induced anticancer activity.

Abstract: Lung injury and fibrosis are common in patients with sickle cell disease (SCD). Fibrocytes, a population of circulating, bone marrow–derived cells, have been linked to development and progression of tissue fibrogenesis and have been implicated in the development of lung fibrosis in preclinical models of SCD. We tested the hypothesis that the levels and activation state of circulating fibrocytes during steady state are associated with abnormal pulmonary function in adults with SCD. In a prospective cohort of steady-state adults with SCD and healthy age- and race-matched control participants, we measured the concentration and activation state of circulating fibrocytes and assessed pulmonary phenotype with pulmonary function tests (PFTs), a respiratory questionnaire, 6-minute walk test, high-resolution chest computed tomography scan, and echocardiogram. Seventy-one adults with SCD and 26 healthy African American control participants were examined. Compared with control participants, patients with SCD demonstrated higher levels of circulating fibrocytes, a significant proportion of which expressed the activation marker α-smooth muscle actin. Within patients with SCD, elevated absolute concentrations of circulating fibrocytes were strongly and independently associated with impaired lung physiology, as measured by PFTs. We conclude that elevated circulating fibrocytes are associated with lung disease in adults with SCD during steady state, consistent with a role for these cells in pathogenesis of lung fibrosis in this disease. Circulating fibrocytes may represent a novel biomarker for progressive pulmonary fibrosis in patients with SCD.

The quality of visual information that is available to an animal is limited by the size of its eyes. Differences in eye size can be observed even between closely related individuals, yet we understand little about how this affects vision. Insects are good models for exploring the effects of size on visual systems because many insect species exhibit size polymorphism. Previous work has been limited by difficulties in determining the 3D structure of eyes. We have developed a novel method based on x-ray microtomography to measure the 3D structure of insect eyes and to calculate predictions of their visual capabilities. We used our method to investigate visual allometry in the bumblebee Bombus terrestris and found that size affects specific aspects of vision, including binocular overlap, optical sensitivity, and dorsofrontal visual resolution. This reveals that differential scaling between eye areas provides flexibility that improves the visual capabilities of larger bumblebees.

Abstract Background Comprehensive and timely rehabilitation for total joint arthroplasty (TJA) is needed to maximize recovery from this elective surgical procedure for hip and knee arthritis. Administrative data do not capture the variation of treatment for rehabilitation across the continuum of care for TJA, so we conducted a survey for physiotherapists to report practice for TJA across the continuum of care. The primary objective was to describe the reported practice of physiotherapy for TJA across the continuum of care within the context of a provincial TJA clinical pathway and highlight possible gaps in care. Method A cross-sectional on-line survey was accessible to licensed physiotherapists in Alberta, Canada for 11 weeks. Physiotherapists who treated at least five patients with TJA annually were asked to complete the survey. The survey consisted of 58 questions grouped into pre-operative, acute care and post-acute rehabilitation. Variation of practice was described in terms of number, duration and type of visits along with goals of care and program delivery methods. Results Of the 80 respondents, 26 (33 %) stated they worked in small centres or rural settings in Alberta with the remaining respondents working in two large urban sites. The primary treatment goal differed for each phase across the continuum of care in that pre-operative phase was directed at improving muscle strength, functional activities were commonly reported for acute care, and post-acute phase was directed at improving joint range-of-motion. Proportionally, more physiotherapists from rural areas treated patients in out-patient hospital departments (59 %), whereas a higher proportion in urban physiotherapists saw patients in private clinics (48 %). Across the continuum of care, treatment was primarily delivered on an individual basis rather than in a group format. Conclusions Variation of practice reported with pre-and post-operative care in the community will stimulate dialogue within the profession as to what is the minimal standard of care to provide patients undergoing TJA.

The quantitative assessment of eye tracking data quality is critical for ensuring accuracy and precision of gaze position measurements. However, researchers often report the eye tracker’s optimal manufacturer’s specifications rather than empirical data about the accuracy and precision of the eye tracking data being presented. Indeed, a recent report indicates that less than half of eye tracking researchers surveyed take the eye tracker’s accuracy into account when determining areas of interest for analysis, an oversight that could impact the validity of reported results and conclusions. Accordingly, we designed a calibration verification protocol to augment independent quality assessment of eye tracking data and examined whether accuracy and precision varied between three age groups of participants. We also examined the degree to which our externally quantified quality assurance metrics aligned with those reported by the manufacturer. We collected data in standard laboratory conditions to demonstrate our method, to illustrate how data quality can vary with participant age, and to give a simple example of the degree to which data quality can differ from manufacturer reported values. In the sample data we collected, accuracy for adults was within the range advertised by the manufacturer, but for school-aged children, accuracy and precision measures were outside this range. Data from toddlers were less accurate and less precise than data from adults. Based on an a priori inclusion criterion, we determined that we could exclude approximately 20% of toddler participants for poor calibration quality quantified using our calibration assessment protocol. We recommend implementing and reporting quality assessment protocols for any eye tracking tasks with participants of any age or developmental ability. We conclude with general observations about our data, recommendations for what factors to consider when establishing data inclusion criteria, and suggestions for stimulus design that can help accommodate variability in calibration. The methods outlined here may be particularly useful for developmental psychologists who use eye tracking as a tool, but who are not experts in eye tracking per se. The calibration verification stimuli and data processing scripts that we developed, along with step-by-step instructions, are freely available for other researchers.

Cancer stem cells (CSCs) correlate with recurrence, metastasis and poor survival in clinical studies. Encouraging results from clinical trials of CSC inhibitors have further validated CSCs as therapeutic targets. ONC201 is a first-in-class small molecule imipridone in Phase I/II clinical trials for advanced cancer. We have previously shown that ONC201 targets self-renewing, chemotherapy-resistant colorectal CSCs via Akt/ERK inhibition and DR5/TRAIL induction. In this study, we demonstrate that the anti-CSC effects of ONC201 involve early changes in stem cell-related gene expression prior to tumor cell death induction. A targeted network analysis of gene expression profiles in colorectal cancer cells revealed that ONC201 downregulates stem cell pathways such as Wnt signaling and modulates genes (ID1, ID2, ID3 and ALDH7A1) known to regulate self-renewal in colorectal, prostate cancer and glioblastoma. ONC201-mediated changes in CSC-related gene expression were validated at the RNA and protein level for each tumor type. Accordingly, we observed inhibition of self-renewal and CSC markers in prostate cancer cell lines and patient-derived glioblastoma cells upon ONC201 treatment. Interestingly, ONC201-mediated CSC depletion does not occur in colorectal cancer cells with acquired resistance to ONC201. Finally, we observed that basal expression of CSC-related genes (ID1, CD44, HES7 and TCF3) significantly correlate with ONC201 efficacy in >1000 cancer cell lines and combining the expression of multiple genes leads to a stronger overall prediction. These proof-of-concept studies provide a rationale for testing CSC expression at the RNA and protein level as a predictive and pharmacodynamic biomarker of ONC201 response in ongoing clinical studies.

INTRODUCTION:Though still high, the infant mortality rate in Guinea-Bissau has declined. We aimed to identify risk factors including vaccination coverage, for infant mortality in the rural population of Guinea-Bissau and assess whether these risk factors changed from 1992-3 to 2002-3. METHODS:The Bandim Health Project (BHP) continuously surveys children in rural Guinea-Bissau. We investigated the association between maternal and infant factors (especially DTP and measles coverage) and infant mortality. Hazard ratios (HR) were calculated using Cox regression. We tested for interactions with sex, age groups (defined by current vaccination schedule) and cohort to assess whether the risk factors were the same for boys and girls, in different age groups in 1992-3 and in 2002-3. RESULTS:The infant mortality rate declined from 148/1000 person years (PYRS) in 1992-3 to 124/1000 PYRS in 2002-3 (HR = 0.88;95%CI:0.77-0.99); this decline was significant for girls (0.77;0.64-0.94) but not for boys (0.97;0.82-1.15) (p = 0.10 for interaction). Risk factors did not differ significantly by cohort in either distribution or effect. Mortality decline was most marked among girls aged 9-11 months (0.56;0.37-0.83). There was no significant mortality decline for girls 1.5-8 months of age (0.93;0.68-1.28) (p = 0.05 for interaction). DTP and measles coverage increased from 1992-3 to 2002-3. CONCLUSIONS:Risk factors did not change with the decline in mortality. Due to beneficial non-specific effects for girls, the increased coverage of measles vaccination may have contributed to the disproportional decline in mortality by sex and age group.

bills, sign multi-­‐year contracts, and make purchasing decisions without having an overall technology plan. That plan includes a technology baseline to fully assess existing technology. A CIO's goal is to align IT with business goals. Businesses must know total cost of ownership and the return on investment for all technology purchases and monthly costs. A business must also be able to manage technology assets and best utilize resources across the business. Teaching students to baseline technology will enable them to track and manage costs, discover errors and waste, and consolidate and improve existing technology.

Introduction: Since the Affordable Care Act was passed, more than 12 million individuals have enrolled in the health insurance marketplace. Without support, many struggle to make an informed plan choice that meets their health and financial needs. Methods: We designed and evaluated a decision aid, Show Me My Health Plans (SMHP), that provides education, preference assessment, and an annual out-of-pocket cost calculator with plan recommendations produced by a tailored, risk-adjusted algorithm incorporating age, gender, and health status. We evaluated whether SMHP compared to HealthCare.gov improved health insurance decision quality and the match between plan choice, needs, and preferences among 328 Missourians enrolling in the marketplace. Results: Participants who used SMHP had higher health insurance knowledge (LS-Mean = 78 vs. 62; P < 0.001), decision self-efficacy (LS-Mean = 83 vs. 75; P < 0.002), confidence in their choice (LS-Mean = 3.5 vs. 2.9; P < 0.001), and improved health insurance literacy (odds ratio = 2.52, P < 0.001) compared to participants using HealthCare.gov . Those using SMHP were 10.3 times more likely to select a silver- or gold-tier plan (P < 0.0001). Discussion: SMHP can improve health insurance decision quality and the odds that consumers select an insurance plan with coverage likely needed to meet their health needs. This study represents a unique context through which to apply principles of decision support to improve health insurance choices.

L’article vise à exposer un travail de recherche amorcé à l’automne 2013 à propos des conditions, des enjeux et des effets de l’intégration des principes de l’innovation ouverte et, plus particulièrement, de l’approche design et du codesign dans le développement des institutions comme les bibliothèques publiques. Il propose dans un premier temps une théorie pragmatique originale du design social, à la frontière du design et de la sociologie, comme sociologie des associations par le design. Il présente ensuite deux démarches de codesign réalisées en 2014 en recherche-intervention dans le cadre de projets de rénovation de bibliothèques d’arrondissement de la Ville de Montréal.

Epigenetic mechanisms, including DNA methylation, histone modification, and microRNAs, play pivotal roles in stem cell biology. Methyl-CpG binding protein 1 (MBD1), an important epigenetic regulator of adult neurogenesis, controls the proliferation and differentiation of adult neural stem/progenitor cells (aNSCs). We recently demonstrated that MBD1 deficiency in aNSCs leads to altered expression of several noncoding microRNAs (miRNAs).Here we show that one of these miRNAs, miR-195, and MBD1 form a negative feedback loop. While MBD1 directly represses the expression of miR-195 in aNSCs, high levels of miR-195 in turn repress the expression of MBD1. Both gain-of-function and loss-of-function investigations show that alterations of the MBD1-miR-195 feedback loop tip the balance between aNSC proliferation and differentiation.Therefore the regulatory loop formed by MBD1 and miR-195 is an important component of the epigenetic network that controls aNSC fate.

Abstract Background HMG‐CoA reductase inhibitors (statins) have pleiotropic effects that are independent of cholesterol‐lowering, including a dose‐dependent effect on angiogenesis. Angiogenesis plays a critical role both in vascularization of the chronically ischemic myocardium and in stabilization of atherosclerotic plaques. Chemokines, a family of structurally‐related cytokine molecules, exert diverse biological functions including control of angiogenesis. The effect of statin therapy on angiogenic and angiostatic chemokines has not been evaluated extensively. We sought to test the hypothesis that, in subjects with hyperlipidemia, statin therapy influences plasma levels of angiogenic and angiostatic chemokines in a dose‐dependent manner. Methods We prospectively collected demographic, angiographic and laboratory data from subjects with a history of hyperlipidemia who were either untreated or on statin therapy. A peripheral blood sample was obtained for measurement of plasma angiogenic and angiostatic chemokines. Multivariable analysis using logistic regression was performed adjusting for the following variables: age, gender, prior myocardial infarction, and chronic administration of aspirin, clopidogrel, insulin, oral hypoglycemic agents, beta‐blockers and calcium channel blockers. Results 168 patients on statin therapy (48 on low‐dose, defined as

Interstitial lung disease is a frequent complication in sickle cell disease and is characterized by vascular remodeling and interstitial fibrosis. Bone marrow-derived fibrocytes have been shown to contribute to the pathogenesis of other interstitial lung diseases. The goal of this study was to define the contribution of fibrocytes to the pathogenesis of sickle cell lung disease.Fibrocytes were quantified and characterized in subjects with sickle cell disease or healthy controls, and in a model of sickle cell disease, the NY1DD mouse. The role of the chemokine ligand CXCL12 in trafficking of fibrocytes and phenotype of lung disease was examined in the animal model. We found elevated concentration of activated fibrocytes in the peripheral blood of subjects with sickle cell disease, which increased further during vaso-occlusive crises. There was a similar elevations in the numbers and activation phenotype of fibrocytes in the bone marrow, blood, and lungs of the NY1DD mouse, both at baseline and under conditions of hypoxia/re-oxygenation. In both subjects with sickle cell disease and the mouse model, fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on most fibrocytes, and CCR2 and CCR7 expressed on a smaller subset of cells. Depletion of the CXCR4 ligand, CXCL12, in the mouse model resulted in a marked reduction of fibrocyte trafficking into the lungs, reduced lung collagen content and improved lung compliance and histology.These data support the notion that activated fibrocytes play a significant role in the pathogenesis of sickle cell lung disease.

Empyema is an increasingly frequent clinical problem worldwide, and has substantial morbidity and mortality. Our objectives were to identify the clinical, surgical and microbiological features, and management outcomes, of empyema.A retrospective observational study over 12 years (1999-2010) was carried out at The Heart Hospital, London, United Kingdom. Patients with empyema were identified by screening the hospital electronic 'Clinical Data Repository'. Demographics, clinical and microbiological characteristics, underlying risk factors, peri-operative blood tests, treatment and outcomes were identified. Univariable and multivariable statistical analyses were performed.Patients (n = 406) were predominantly male (74.1%); median age = 53 years (IQR = 37-69). Most empyema were community-acquired (87.4%) and right-sided (57.4%). Microbiological diagnosis was obtained in 229 (56.4%) patients, and included streptococci (16.3%), staphylococci (15.5%), gram-negative organisms (8.9%), anaerobes (5.7%), pseudomonads (4.4%) and mycobacteria (9.1%); 8.4% were polymicrobial. Most (68%) cases were managed by open thoracotomy and decortication. Video-assisted thoracoscopic surgery (VATS) reduced hospitalisation from 10 to seven days (P = 0.0005). All-cause complication rate was 25.1%, and 28 day mortality 5.7%. Predictors of early mortality included: older age (P = 0.006), major co-morbidity (P = 0.01), malnutrition (P = 0.001), elevated red cell distribution width (RDW, P

In patients with chronic ischemic heart disease (IHD), the presence and extent of spontaneously visible coronary collaterals are powerful determinants of clinical outcome. There is marked heterogeneity in the recruitment of coronary collaterals amongst patients with similar degrees of coronary artery stenoses, but the biological basis of this heterogeneity is not known. Chemokines are potent mediators of vascular remodeling in diverse biological settings. Their role in coronary collateralization has not been investigated. We sought to determine whether plasma levels of angiogenic and angiostatic chemokines are associated with of the presence and extent of coronary collaterals in patients with chronic IHD.We measured plasma concentrations of angiogenic and angiostatic chemokine ligands in 156 consecutive subjects undergoing coronary angiography with at least one ≥90% coronary stenosis and determined the presence and extent of spontaneously visible coronary collaterals using the Rentrop scoring system. Eighty-eight subjects (56%) had evidence of coronary collaterals. In a multivariable regression model, the concentration of the angiogenic ligands CXCL5, CXCL8 and CXCL12, hyperlipidemia, and an occluded artery were associated with the presence of collaterals; conversely, the concentration of the angiostatic ligand CXCL11, interferon-γ, hypertension and diabetes were associated with the absence of collaterals (ROC area 0.91). When analyzed according to extent of collateralization, higher Rentrop scores were significantly associated with increased concentration of the angiogenic ligand CXCL1 (p

Mycobacteriophages are viruses that infect mycobacterial hosts such as Mycobacterium smegmatis and Mycobacterium tuberculosis. All mycobacteriophages characterized to date are dsDNA tailed phages, and have either siphoviral or myoviral morphotypes. However, their genetic diversity is considerable, and although sixty-two genomes have been sequenced and comparatively analyzed, these likely represent only a small portion of the diversity of the mycobacteriophage population at large. Here we report the isolation, sequencing and comparative genomic analysis of 18 new mycobacteriophages isolated from geographically distinct locations within the United States. Although no clear correlation between location and genome type can be discerned, these genomes expand our knowledge of mycobacteriophage diversity and enhance our understanding of the roles of mobile elements in viral evolution. Expansion of the number of mycobacteriophages grouped within Cluster A provides insights into the basis of immune specificity in these temperate phages, and we also describe a novel example of apparent immunity theft. The isolation and genomic analysis of bacteriophages by freshman college students provides an example of an authentic research experience for novice scientists.

Chemokines have been found to exert direct, defensin-like antimicrobial activity in vitro, suggesting that, in addition to orchestrating cellular accumulation and activation, chemokines may contribute directly to the innate host response against infection. No observations have been made, however, demonstrating direct chemokine-mediated promotion of host defense in vivo. Here, we show that the murine interferon-inducible CXC chemokines CXCL9, CXCL10, and CXCL11 each exert direct antimicrobial effects in vitro against Bacillus anthracis Sterne strain spores and bacilli including disruptions in spore germination and marked reductions in spore and bacilli viability as assessed using CFU determination and a fluorometric assay of metabolic activity. Similar chemokine-mediated antimicrobial activity was also observed against fully virulent Ames strain spores and encapsulated bacilli. Moreover, antibody-mediated neutralization of these CXC chemokines in vivo was found to significantly increase host susceptibility to pulmonary B. anthracis infection in a murine model of inhalational anthrax with disease progression characterized by systemic bacterial dissemination, toxemia, and host death. Neutralization of the shared chemokine receptor CXCR3, responsible for mediating cellular recruitment in response to CXCL9, CXCL10, and CXCL11, was not found to increase host susceptibility to inhalational anthrax. Taken together, our data demonstrate a novel, receptor-independent antimicrobial role for the interferon-inducible CXC chemokines in pulmonary innate immunity in vivo. These data also support an immunomodulatory approach for effectively treating and/or preventing pulmonary B. anthracis infection, as well as infections caused by pathogenic and potentially, multi-drug resistant bacteria including other spore-forming organisms.