TGF-b2 induction regulates invasiveness of theileria-transformed leukocytes and disease susceptibility

Theileria parasites invade and transform bovine leukocytes causing either East Coast fever (T. parva), or tropical theileriosis (T. annulata). Susceptible animals usually die within weeks of infection, but indigenous infected cattle show markedly reduced pathology, suggesting that host genetic factors may cause disease susceptibility. Attenuated live vaccines are widely used to control tropical theileriosis and attenuation is associated with reduced invasiveness of infected macrophages in vitro. Disease pathogenesis is therefore linked to aggressive invasiveness, rather than uncontrolled proliferation of Theileria-infected leukocytes. We show that the invasive potential of Theileria-transformed leukocytes involves TGF-b signalling. Attenuated live vaccine lines express reduced TGF-b2 and their invasiveness can be rescued with exogenous TGF-b. Importantly, infected macrophages from disease susceptible Holstein-Friesian (HF) cows express more TGF-b2 and traverse Matrigel with great efficiency compared to those from disease-resistant Sahiwal cattle. Thus, TGF-b2 levels correlate with disease susceptibility. Using fluorescence and time-lapse video microscopy we show that Theileria-infected, disease-susceptible HF macrophages exhibit increased actin dynamics in their lamellipodia and podosomal adhesion structures and develop more membrane blebs. TGF-b2-associated invasiveness in HF macrophages has a transcription-independent element that relies on cytoskeleton remodelling via activation of Rho kinase (ROCK). We propose that a TGF-b autocrine loop confers an amoeboid-like motility on Theileria-infected leukocytes, which combines with MMP-dependent motility to drive invasiveness and virulence

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012." DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality

Learner control in animated multimedia instructions

The interactivity principle in multimedia learning states that giving learners control over pace and order of instructions decreases cognitive load and increases transfer performance. We tested this guideline by comparing a learner-paced instruction with a system-paced instruction. Time-on-task and interactive behavior were logged, and were also related to interest, prior knowledge, and cognitive involvement. We successfully replicated the interactivity principle in terms of better transfer. However, this coincided with a large increase in time-on-task. Also, large individual differences existed in the use of learner control options, which were mostly unrelated to the other variables. Thus, the benefits of introducing learner control in multimedia learning are at the expense of learning efficiency, and it remains unclear for whom the interactivity principle works best

Weekends affect mortality risk and chance of discharge in critically ill patients: a retrospective study in the Austrian registry for intensive care.

BACKGROUND: In this study, we primarily investigated whether ICU admission or ICU stay at weekends (Saturday and Sunday) is associated with a different risk of ICU mortality or chance of ICU discharge than ICU admission or ICU stay on weekdays (Monday to Friday). Secondarily, we analysed whether weekend ICU admission or ICU stay influences risk of hospital mortality or chance of hospital discharge. METHODS: A retrospective study was performed for all adult patients admitted to 119 ICUs participating in the benchmarking project of the Austrian Centre for Documentation and Quality Assurance in Intensive Care (ASDI) between 2012 and 2015. Readmissions to the ICU during the same hospital stay were excluded. RESULTS: In a multivariable competing risk analysis, a strong weekend effect was observed. Patients admitted to ICUs on Saturday or Sunday had a higher mortality risk after adjustment for severity of illness by Simplified Acute Physiology Score (SAPS) 3, year, month of the year, type of admission, ICU, and weekday of death or discharge. Hazard ratios (95% confidence interval) for death in the ICU following admission on a Saturday or Sunday compared with Wednesday were 1.15 (1.08-1.23) and 1.11 (1.03-1.18), respectively. Lower hazard ratios were observed for dying on a Saturday (0.93 (0.87-1.00)) or Sunday (0.85 (0.80-0.91)) compared with Wednesday. This is probably related to the reduced chance of being discharged from the ICU at the weekend (0.63 (0.62-064) for Saturday and 0.56 (0.55-0.57) for Sunday). Similar results were found for hospital mortality and hospital discharge following ICU admission. CONCLUSIONS: Patients admitted to ICUs at weekends are at increased risk of death in both the ICU and the hospital even after rigorous adjustment for severity of illness. Conversely, death in the ICU and discharge from the ICU are significantly less likely at weekends

A Discrete Event Simulation model to evaluate the treatment pathways of patients with Cataract in the United Kingdom

Background The number of people affected by cataract in the United Kingdom (UK) is growing rapidly due to ageing population. As the only way to treat cataract is through surgery, there is a high demand for this type of surgery and figures indicate that it is the most performed type of surgery in the UK. The National Health Service (NHS), which provides free of charge care in the UK, is under huge financial pressure due to budget austerity in the last decade. As the number of people affected by the disease is expected to grow significantly in coming years, the aim of this study is to evaluate whether the introduction of new processes and medical technologies will enable cataract services to cope with the demand within the NHS funding constraints. Methods We developed a Discrete Event Simulation model representing the cataract services pathways at Leicester Royal Infirmary Hospital. The model was inputted with data from national and local sources as well as from a surgery demand forecasting model developed in the study. The model was verified and validated with the participation of the cataract services clinical and management teams. Results Four scenarios involving increased number of surgeries per half-day surgery theatre slot were simulated. Results indicate that the total number of surgeries per year could be increased by 40% at no extra cost. However, the rate of improvement decreases for increased number of surgeries per half-day surgery theatre slot due to a higher number of cancelled surgeries. Productivity is expected to improve as the total number of doctors and nurses hours will increase by 5 and 12% respectively. However, non-human resources such as pre-surgery rooms and post-surgery recovery chairs are under-utilized across all scenarios. Conclusions Using new processes and medical technologies for cataract surgery is a promising way to deal with the expected higher demand especially as this could be achieved with limited impact on costs. Non-human resources capacity need to be evenly levelled across the surgery pathway to improve their utilisation. The performance of cataract services could be improved by better communication with and proactive management of patients.Peer reviewedFinal Published versio

Evaluation of simplified acute physiology score 3 performance: a systematic review of external validation studies

Introduction: Simplified Acute Physiology Score 3 (SAPS 3) was the first critical care prognostic model developed from worldwide data. We aimed to systematically review studies that assessed the prognostic performance of SAPS 3 general and customized models for predicting hospital mortality in adult patients admitted to the ICU. Methods: Medline, Lilacs, Scielo and Google Scholar were searched to identify studies which assessed calibration and discrimination of general and customized SAPS 3 equations. Additionally, we decided to evaluate the correlation between trial size (number of included patients) and the Hosmer-Lemeshow (H-L) statistics value of the SAPS 3 models. Results: A total of 28 studies were included. Of these, 11 studies (42.8\%) did not find statistically significant mis-calibration for the SAPS 3 general equation. There was a positive correlation between number of included patients and higher H-L statistics, that is, a statistically significant mis-calibration of the model (r = 0.747, P < 0.001). Customized equations for major geographic regions did not have statistically significant departures from perfect calibration in 9 of 19 studies. Five studies (17.9\%) developed a regional customization and in all of them this new model was not statistically different from a perfect calibration for their populations. Discrimination was at least very good in 24 studies (85.7\%). Conclusions: Statistically significant departure from perfect calibration for the SAPS 3 general equation was common in validation studies and was correlated with larger studies, as should be expected, since H-L statistics (both C and H) are strongly dependent on sample size This finding was also present when major geographic customized equations were evaluated. Local customizations, on the other hand, improved SAPS 3 calibration. Discrimination was almost always very good or excellent, which gives excellent perspectives for local customization when a precise local estimate is needed.publishersversionpublishe

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT