Intestinal organoids model human responses to infection by commensal and Shiga toxin producing Escherichia coli

Infection with Shiga toxin (Stx) producing Escherichia coli O157:H7 can cause the potentially fatal complication hemolytic uremic syndrome, and currently only supportive therapy is available. Lack of suitable animal models has hindered study of this disease. Induced human intestinal organoids (iHIOs), generated by in vitro differentiation of pluripotent stem cells, represent differentiated human intestinal tissue. We show that iHIOs with addition of human neutrophils can model E. coli intestinal infection and innate cellular responses. Commensal and O157:H7 introduced into the iHIO lumen replicated rapidly achieving high numbers. Commensal E. coli did not cause damage, and were completely contained within the lumen, suggesting defenses, such as mucus production, can constrain non-pathogenic strains. Some O157:H7 initially co-localized with cellular actin. Loss of actin and epithelial integrity was observed after 4 hours. O157:H7 grew as filaments, consistent with activation of the bacterial SOS stress response. SOS is induced by reactive oxygen species (ROS), and O157:H7 infection increased ROS production. Transcriptional profiling (RNAseq) demonstrated that both commensal and O157:H7 upregulated genes associated with gastrointestinal maturation, while infection with O157:H7 upregulated inflammatory responses, including interleukin 8 (IL-8). IL-8 is associated with neutrophil recruitment, and infection with O157:H7 resulted in recruitment of human neutrophils into the iHIO tissue

Assessing differential attrition in clinical trials: self-monitoring of oral anticoagulation and type II diabetes

Background: Analyzing drop out rates and when they occur may give important information about the patient characteristics and trial characteristics that affect the overall uptake of an intervention. Methods: We searched Medline and the Cochrane library from the beginning of the databases to May 2006 for published systematic reviews that compared the effects of self-monitoring (self-testing) or self-management (self-testing and self-dosage) of oral anticoagulation or self-monitored blood glucose in type 2 diabetics who were not using insulin. We assessed all study withdrawals pre-randomization and post randomization and sought information on the reasons for discontinuation of all participants. To measure the differential between groups in attrition we used the relative attrition (RA), which is equivalent to relative risk but uses attrition as the outcome (i.e. attrition in intervention group/ attrition in control group). We determined the percentage drop outs for control and intervention groups and used DerSimonian and Laird random effects models to estimate a pooled relative attrition. L'abbe type plots created in R (version 2.0.2) were used to represent the difference in the relative attrition among the trials with 95% confidence areas and weights derived from the random effects model. Results: With self-monitoring of blood glucose in type 2 diabetes, attrition ranged from 2.3% to 50.0% in the intervention groups and 0% to 40.4% in the control groups. There was no significant difference between the intervention and control, with an overall RA of 1.18 [95% CI, 0.70-2.01]. With self-monitoring of oral anticoagulation attrition ranged from 0% to 43.2% in the intervention groups, and 0% to 21.4% in the control group. The RA was significantly greater in the intervention group, combined RA, 6.05 [95% CI, 2.53-14.49]. Conclusion: This paper demonstrates the use of relative attrition as a new tool in systematic review methodology which has the potential to identify patient, intervention and trial characteristics which influences attrition in trials

Intra-individual effects of food upon the pharmacokinetics of rifampicin and isoniazid

Background: Poor response to TB therapy might be attributable to subtherapeutic levels in drug-compliant patients. Pharmacokinetic parameters can be affected by comorbidities or the interaction of drugs with food. Objectives: This study aimed to determine the effect of food intake upon pharmacokinetics of rifampicin and isoniazid in a Peruvian population with TB. Methods: Rifampicin and isoniazid levels were analysed at 2, 4 and 6 h after drug intake in both fasting and non-fasting states using LC-MS methods. Results: Sixty patients participated in the study. The median rifampicin Cmax and AUC0–6 were higher during fasting than non-fasting: 7.02 versus 6.59 mg/L (P = 0.054) and 28.64 versus 24.31 mg·h/L (P = 0.002). There was a statistically significant delay overall of non-fasting Tmax compared with the fasting state Tmax (P = 0.005). In the multivariate analysis, besides the effect of fasting, Cmax for females was 20% higher than for males (P = 0.03). Concerning isoniazid, there were significant differences in the Cmax during non-fasting (median = 3.51 mg/L) compared with fasting (4.54 mg/L). The isoniazid dose received had an effect upon the isoniazid levels (1.26, P = 0.038). In the multivariate analysis, isoniazid exposure during fasting was found to be 14% higher than during non-fasting (CI = 1.02–1.28, P < 0.001). Neither radiological extent of the disease nor consumption of food with drug intake nor pharmacokinetics of rifampicin or isoniazid was associated with a poorer treatment outcome. Conclusions: Rifampicin in particular and isoniazid pharmacokinetics were significantly affected by the intake of the drug with food between and within individuals

Rape and respectability: ideas about sexual violence and social class

Women on low incomes are disproportionately represented among sexual violence survivors, yet feminist research on this topic has paid very little attention to social class. This article blends recent research on class, gender and sexuality with what we know about sexual violence. It is argued that there is a need to engage with classed distinctions between women in terms of contexts for and experiences of sexual violence, and to look at interactions between pejorative constructions of working-class sexualities and how complainants and defendants are perceived and treated. The classed division between the sexual and the feminine, drawn via the notion of respectability, is applied to these issues. This piece is intended to catalyse further research and debate, and raises a number of questions for future work on sexual violence and social class

Minithoracotomy for mitral valve repair improves inpatient and postdischarge economic savings

ObjectiveSmall series of thoracotomy for mitral valve repair have demonstrated clinical benefit. This multi-institutional administrative database analysis compares outcomes of thoracotomy and sternotomy approaches for mitral repair.MethodsThe Premier database was queried from 2007 to 2011 for mitral repair hospitalizations. Premier contains billing, cost, and coding data from more than 600 US hospitals, totaling 25 million discharges. Thoracotomy and sternotomy approaches were identified through expert rules; robotics were excluded. Propensity matching on baseline characteristics was performed. Regression analysis of surgical approach on outcomes and costs was modeled.ResultsExpert rule analysis positively identified thoracotomy in 847 and sternotomy in 566. Propensity matching created 2 groups of 367. Mortalities were similar (thoracotomy 1.1% vs sternotomy 1.9%). Sepsis and other infections were significantly lower with thoracotomy (1.1% vs 4.4%). After adjustment for hospital differences, thoracotomy carried a 17.2% lower hospitalization cost (−$8289) with a 2-day stay reduction. Readmission rates were significantly lower with thoracotomy (26.2% vs 35.7% at 30 days and 31.6% vs 44.1% at 90 days). Thoracotomy was more common in southern and northeastern hospitals (63% vs 37% and 64% vs 36%, respectively), teaching hospitals (64% vs 36%) and larger hospitals (>600 beds, 78% vs 22%).ConclusionsRelative to sternotomy, thoracotomy for mitral repairs provides similar mortality, less morbidity, fewer infections, shorter stay, and significant cost savings during primary admission. The markedly lower readmission rates for thoracotomy will translate into additional institutional cost savings when a penalty on hospitals begins under the Affordable Care Act's Hospital Readmissions Reduction Program

Going back to school – an opportunity for lifelong learning for people with dementia in Denmark (Innovative practice)

The provision of lifelong learning for older people is often promoted as a way of engaging socially and maintaining cognitive function. The concept is also used with people with dementia, but is often limited to short-term programmes. Innovative practice from Denmark takes this concept further, offering people with early stage dementia the opportunity to return to school to attend classes in cognitive training, music, art and woodcraft. A pilot study conducted by the school of teaching and communication (VUK), offers evidence for the benefits of prolonged educational programmes for people with dementia in maintaining decision making, cognitive function and social interactions, with limited evidence of the impact on memory. Further evidence is required to understand the impact of a person with dementia attending school as a student and to understand if this concept is transferrable to a different cultural setting

An Unbiased Survey of 500 Nearby Stars for Debris Disks: A JCMT Legacy Program

We present the scientific motivation and observing plan for an upcoming detection survey for debris disks using the James Clerk Maxwell Telescope. The SCUBA-2 Unbiased Nearby Stars (SUNS) Survey will observe 500 nearby main sequence and sub-giant stars (100 of each of the A, F, G, K and M spectral classes) to the 850 micron extragalactic confusion limit to search for evidence of submillimeter excess, an indication of circumstellar material. The survey distance boundaries are 8.6, 16.5, 22, 25 and 45 pc for M, K, G, F and A stars, respectively, and all targets lie between the declinations of -40 deg to 80 deg. In this survey, no star will be rejected based on its inherent properties: binarity, presence of planetary companions, spectral type or age. This will be the first unbiased survey for debris disks since IRAS. We expect to detect ~125 debris disks, including ~50 cold disks not detectable in current shorter wavelength surveys. A substantial amount of complementary data will be required to constrain the temperatures and masses of discovered disks. High resolution studies will likely be required to resolve many of the disks. Therefore, these systems will be the focus of future observational studies using a variety of observatories to characterize their physical properties. For non-detected systems, this survey will set constraints (upper limits) on the amount of circumstellar dust, of typically 200 times the Kuiper Belt mass, but as low as 10 times the Kuiper Belt mass for the nearest stars in the sample (approximately 2 pc).Comment: 11 pages, 7 figures (3 color), accepted by the Publications of the Astronomical Society of the Pacifi

The Relationship Between Physical Activity and Diet and Young Children\u27s Cognitive Development: A Systematic Review

Objective Given the high prevalence of suboptimal nutrition and low activity levels in children, we systematically reviewed the literature on the relationship between physical activity and dietary patterns and cognitive development in early childhood (six months to five years). Methods In February 2016, we conducted two different searches of MEDLINE, PsycINFO, and ERIC. Each search included either physical activity (including gross motor skills) or diet terms, and neurocognitive development outcome terms. Included studies were in English, published since 2005, and of any study design in which the physical activity or diet measure occurred prior to age five. Results For physical activity, twelve studies (5 cross-sectional, 3 longitudinal and 4 experimental) were included. Eleven studies reported evidence suggesting that physical activity or gross motor skills are related to cognition or learning. Both acute bouts and longer term exposures showed benefit. For diet, eight studies were included consisting of secondary analyses from longitudinal cohort studies. A healthier dietary pattern was associated with better cognitive outcomes in all studies, although some of the reported associations were weak and the measures used varied across the studies. Conclusions Physical activity and healthy diets in early childhood are associated with better cognitive outcomes in young children. The paucity of literature and the variability in the type and quality of measures used highlight the need for more rigorous research. Given that the early childhood years are critical for both obesity prevention and neurocognitive development, evidence that the same healthy behaviors could promote both should inform future interventions. Keywords Nutrition; Physical activity; Childhood obesity; Cognitive development; Executive function; Early learnin

Data assimilation and agent-based modelling: towards the incorporation of categorical agent parameters

This paper explores the use of a particle filter—a data assimilation method—to incorporate real-time data into an agent-based model. We apply the method to a simulation of real pedestrians moving through the concourse of Grand Central Terminal in New York City (USA). The results show that the particle filter does not perform well due to (i) the unpredictable behaviour of some pedestrians and (ii) because the filter does not optimise the categorical agent parameters that are characteristic of this type of model. This problem only arises because the experiments use real-world pedestrian movement data, rather than simulated, hypothetical data, as is more common. We point to a potential solution that involves resampling some of the variables in a particle, such as the locations of the agents in space, but keeps other variables such as the agents’ choice of destination. This research illustrates the importance of including real-world data and provides a proof of concept for the application of an improved particle filter to an agent-based model. The obstacles and solutions discussed have important implications for future work that is focused on building large-scale real-time agent-based models

Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration

Tuberculosis (TB) treatment is long and complex, typically involving a combination of drugs taken for 6 months. Improved drug regimens to shorten and simplify treatment are urgently required, however a major challenge to TB drug development is the lack of predictive pre-clinical tools. To address this deficiency, we have adopted a new high-content imaging-based approach capable of defining the killing kinetics of first line anti-TB drugs against intracellular Mycobacterium tuberculosis (Mtb) residing inside macrophages. Through use of this pharmacokinetic-pharmacodynamic (PK-PD) approach we demonstrate that the killing dynamics of the intracellular Mtb sub-population is critical to predicting clinical TB treatment duration. Integrated modelling of intracellular Mtb killing alongside conventional extracellular Mtb killing data, generates the biphasic responses typical of those described clinically. Our model supports the hypothesis that the use of higher doses of rifampicin (35?mg/kg) will significantly reduce treatment duration. Our described PK-PD approach offers a much needed decision making tool for the identification and prioritisation of new therapies which have the potential to reduce TB treatment duration