Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis

Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two

Liver fibrosis indices and outcomes after primary intracerebral hemorrhage

Background and Purpose- Cirrhosis-clinically overt, advanced liver disease-is associated with an increased risk of hemorrhagic stroke and poor stroke outcomes. We sought to investigate whether subclinical liver disease, specifically liver fibrosis, is associated with clinical and radiological outcomes in patients with primary intracerebral hemorrhage. Methods- We performed a retrospective cohort study using data from the Virtual International Stroke Trials Archive-Intracerebral Hemorrhage. We included adult patients with primary intracerebral hemorrhage presenting within 6 hours of symptom onset. We calculated 3 validated fibrosis indices-Aspartate Aminotransferase-Platelet Ratio Index, Fibrosis-4 score, and Nonalcoholic Fatty Liver Disease Fibrosis Score-and modeled them as continuous exposure variables. Primary outcomes were admission hematoma volume and hematoma expansion. Secondary outcomes were mortality, and the composite of major disability or death, at 90 days. We used linear and logistic regression models adjusted for previously established risk factors. Results- Among 432 patients with intracerebral hemorrhage, the mean Aspartate Aminotransferase-Platelet Ratio Index, Fibrosis-4, and Nonalcoholic Fatty Liver Disease Fibrosis Score values on admission reflected intermediate probabilities of fibrosis, whereas standard hepatic assays and coagulation parameters were largely normal. After adjusting for potential confounders, Aspartate Aminotransferase-Platelet Ratio Index was associated with hematoma volume (β, 0.20 [95% CI, 0.04-0.36]), hematoma expansion (odds ratio, 1.6 [95% CI, 1.1-2.3]), and mortality (odds ratio, 1.8 [95% CI, 1.1-2.7]). Fibrosis-4 was also associated with hematoma volume (β, 0.27 [95% CI, 0.07-0.47]), hematoma expansion (odds ratio, 1.9 [95% CI, 1.2-3.0]), and mortality (odds ratio, 2.0 [95% CI, 1.1-3.6]). Nonalcoholic Fatty Liver Disease Fibrosis Score was not associated with any outcome. Indices were not associated with the composite of major disability or death. Conclusions- In patients with largely normal liver chemistries, 2 liver fibrosis indices were associated with admission hematoma volume, hematoma expansion, and mortality after intracerebral hemorrhage

Improved analysis of bacterial CGH data beyond the log-ratio paradigm

<p>Abstract</p> <p>Background</p> <p>Existing methods for analyzing bacterial CGH data from two-color arrays are based on log-ratios only, a paradigm inherited from expression studies. We propose an alternative approach, where microarray signals are used in a different way and sequence identity is predicted using a supervised learning approach.</p> <p>Results</p> <p>A data set containing 32 hybridizations of sequenced versus sequenced genomes have been used to test and compare methods. A ROC-analysis has been performed to illustrate the ability to rank probes with respect to Present/Absent calls. Classification into Present and Absent is compared with that of a gaussian mixture model.</p> <p>Conclusion</p> <p>The results indicate our proposed method is an improvement of existing methods with respect to ranking and classification of probes, especially for multi-genome arrays.</p

mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype

Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response, but it can also show pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find new SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA-binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells in both tumour-suppressive and tumour-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses

Clustering and meso-level variables in cross-sectional surveys: an example of food aid during the Bosnian crisis

<p>Abstract</p> <p>Background</p> <p>Focus groups, rapid assessment procedures, key informant interviews and institutional reviews of local health services provide valuable insights on health service resources and performance. A long-standing challenge of health planning is to combine this sort of qualitative evidence in a unified analysis with quantitative evidence from household surveys. A particular challenge in this regard is to take account of the neighbourhood or clustering effects, recognising that these can be informative or incidental.</p> <p>Methods</p> <p>An example of food aid and food sufficiency from the Bosnian emergency (1995-96) illustrates two Lamothe cluster-adjustments of the Mantel Haenszel (MH) procedure, one assuming a fixed odds ratio and the other allowing for informative clustering by not assuming a fixed odds ratio. We compared these with conventional generalised estimating equations and a generalised linear mixed (GLMM) model, using a Laplace adjustment.</p> <p>Results</p> <p>The MH adjustment assuming incidental clustering generated a final model very similar to GEE. The adjustment that does not assume a fixed odds ratio produced a final multivariate model and effect sizes very similar to GLMM.</p> <p>Discussion</p> <p>In medium or large data sets with stratified last stage random sampling, the cluster adjusted MH is substantially more conservative than the naïve MH computation. In the example of food aid in the Bosnian crisis, the cluster adjusted MH that does not assume a fixed odds ratio produced similar results to the GLMM, which identified informative clustering.</p

Time esophageal pH < 4 overestimates the prevalence of pathologic esophageal reflux in subjects with gastroesophageal reflux disease treated with proton pump inhibitors

<p>Abstract</p> <p>Background</p> <p>A Stanford University study reported that in asymptomatic GERD patients who were being treated with a proton pump inhibitor (PPI), 50% had pathologic esophageal acid exposure.</p> <p>Aim</p> <p>We considered the possibility that the high prevalence of pathologic esophageal reflux might simply have resulted from calculating acidity as time pH < 4.</p> <p>Methods</p> <p>We calculated integrated acidity and time pH < 4 from the 49 recordings of 24-hour gastric and esophageal pH from the Stanford study as well as from another study of 57 GERD subjects, 26 of whom were treated for 8 days with 20 mg omeprazole or 20 mg rabeprazole in a 2-way crossover fashion.</p> <p>Results</p> <p>The prevalence of pathologic 24-hour esophageal reflux in both studies was significantly higher when measured as time pH < 4 than when measured as integrated acidity. This difference was entirely attributable to a difference between the two measures during the nocturnal period. Nocturnal gastric acid breakthrough was not a useful predictor of pathologic nocturnal esophageal reflux.</p> <p>Conclusion</p> <p>In GERD subjects treated with a PPI, measuring time esophageal pH < 4 will significantly overestimate the prevalence of pathologic esophageal acid exposure over 24 hours and during the nocturnal period.</p

Gravity Amplitudes from a Gaussian Matrix Model

We reformulate MHV scattering amplitudes in 4D gauge theory and supergravity as correlation functions of bilinear operators in a supersymmetric gaussian matrix model. The model retains the symmetries of an S(4) of radius L and the matrix variables are represented as linear operators acting on a finite-dimensional Hilbert space. Bilinear fields of the model generate a current algebra. In the large N double scaling limit where l_pl ~ L / sqrt(N) is held fixed, there is an emergent flat 4D space-time with a built in short distance cutoff.Comment: v3: 55 pages, 4 figures, clarifications adde

The use of a Psoroptes ovis serodiagnostic test for the analysis of a natural outbreak of sheep scab

<p>Abstract</p> <p>Background</p> <p>Sheep scab is a highly contagious disease of sheep caused by the ectoparasitic mite <it>Psoroptes ovis</it>. The disease is endemic in the UK and has significant economic impact through its effects on performance and welfare. Diagnosis of sheep scab is achieved through observation of clinical signs e.g. itching, pruritis and wool loss and ultimately through the detection of mites in skin scrapings. Early stages of infestation are often difficult to diagnose and sub-clinical animals can be a major factor in disease spread. The development of a diagnostic assay would enable farmers and veterinarians to detect disease at an early stage, reducing the risk of developing clinical disease and limiting spread.</p> <p>Methods</p> <p>Serum samples were obtained from an outbreak of sheep scab within an experimental flock (n = 480 (3 samples each from 160 sheep)) allowing the assessment, by ELISA of sheep scab specific antibody prior to infestation, mid-outbreak (combined with clinical assessment) and post-treatment.</p> <p>Results</p> <p>Analysis of pre-infestation samples demonstrated low levels of potential false positives (3.8%). Of the 27 animals with clinical or behavioural signs of disease 25 tested positive at the mid-outbreak sampling period, however, the remaining 2 sheep tested positive at the subsequent sampling period. Clinical assessment revealed the absence of clinical or behavioural signs of disease in 132 sheep, whilst analysis of mid-outbreak samples showed that 105 of these clinically negative animals were serologically positive, representing potential sub-clinical infestations.</p> <p>Conclusions</p> <p>This study demonstrates that this ELISA test can effectively diagnose sheep scab in a natural outbreak of disease, and more importantly, highlights its ability to detect sub-clinically infested animals. This ELISA, employing a single recombinant antigen, represents a major step forward in the diagnosis of sheep scab and may prove to be critical in any future control program.</p

Can a quality improvement project impact maternal and child health outcomes at scale in northern Ghana?

Background Quality improvement (QI) interventions are becoming more common in low- and middle-income countries, yet few studies have presented impact evaluations of these approaches. In this paper, we present an impact evaluation of a scale-up phase of ‘Project Fives Alive!’, a QI intervention in Ghana that aims to improve maternal and child health outcomes. ‘Project Fives Alive!’ employed a QI methodology to recognize barriers to care-seeking and care provision at the facility level and then to identify, test and implement simple and low-cost local solutions that address the barriers. Methods A quasi-experimental design, multivariable interrupted time series analysis, with data coming from 744 health facilities and controlling for potential confounding factors, was used to study the effect of the project. The key independent variables were the change categories (interventions implemented) and implementation phase – Wave 2a (early phase) versus Wave 2b (later phase). The outcomes studied were early antenatal care (ANC), skilled delivery, facility-level under-five mortality and attendance of underweight infants at child welfare clinics. We stratified the analysis by facility type, namely health posts, health centres and hospitals. Results Several of the specific change categories were significantly associated with improved outcomes. For example, three of five change categories (early ANC, four or more ANC visits and skilled delivery/immediate postnatal care (PNC)) for health posts and two of five change categories (health education and triage) for hospitals were associated with increased skilled delivery. These change categories were associated with increases in skilled delivery varying from 28% to 58%. PNC changes for health posts and health centres were associated with greater attendance of underweight infants at child welfare clinics. The triage change category was associated with increased early antenatal care in hospitals. Intensity, the number of change categories tested, was associated with increased skilled delivery in health centres and reduced under-five mortality in hospitals. Conclusions Using an innovative evaluation technique we determined that ‘Project Fives Alive!’ demonstrated impact at scale for the outcomes studied. The QI approach used by this project should be considered by other low- and middle-income countries in their efforts to improve maternal and child health