Embryonic/fetal mortality and intrauterine growth restriction is not exclusive to the CBA/J sub-strain in the CBA × DBA model.

Inbred strains of mice are powerful models for understanding human pregnancy complications. For example, the exclusive mating of CBA/J females to DBA/2J males increases fetal resorption to 20-35% with an associated decline in placentation and maintenance of maternal Th1 immunity. More recently other complications of pregnancy, IUGR and preeclampsia, have been reported in this model. The aim of this study was to qualify whether the CBA/CaH substrain female can substitute for CBA/J to evoke a phenotype of embryonic/fetal mortality and IUGR. (CBA/CaH × DBA/2J) F1 had significantly higher embryonic/fetal mortality mortality (p = 0.0063), smaller fetuses (p  10th percentile). In addition, placentae of "normal-weight" (CBA/CaH × DBA/2J) F1 were significantly smaller (p < 0.0006) with a greater proportion of labyrinth (p = 0.0128) and an 11-fold increase in F4/80 + macrophage infiltration (p < 0.0001) when compared to placentae of (CBA/CaH × Balb/c) F1. In conclusion, the embryonic/fetal mortality and IUGR phenotype is not exclusive to CBA/J female mouse, and CBA/CaH females can be substituted to provide a model for the assessment of novel therapeutics

Game theory of mind

This paper introduces a model of ‘theory of mind’, namely, how we represent the intentions and goals of others to optimise our mutual interactions. We draw on ideas from optimum control and game theory to provide a ‘game theory of mind’. First, we consider the representations of goals in terms of value functions that are prescribed by utility or rewards. Critically, the joint value functions and ensuing behaviour are optimised recursively, under the assumption that I represent your value function, your representation of mine, your representation of my representation of yours, and so on ad infinitum. However, if we assume that the degree of recursion is bounded, then players need to estimate the opponent's degree of recursion (i.e., sophistication) to respond optimally. This induces a problem of inferring the opponent's sophistication, given behavioural exchanges. We show it is possible to deduce whether players make inferences about each other and quantify their sophistication on the basis of choices in sequential games. This rests on comparing generative models of choices with, and without, inference. Model comparison is demonstrated using simulated and real data from a ‘stag-hunt’. Finally, we note that exactly the same sophisticated behaviour can be achieved by optimising the utility function itself (through prosocial utility), producing unsophisticated but apparently altruistic agents. This may be relevant ethologically in hierarchal game theory and coevolution

Spatial analysis of bladder, kidney, and pancreatic cancer on upper Cape Cod: an application of generalized additive models to case-control data

<p>Abstract</p> <p>Background</p> <p>In 1988, elevated cancer incidence in upper Cape Cod, Massachusetts prompted a large epidemiological study of nine cancers to investigate possible environmental risk factors. Positive associations were observed, but explained only a portion of the excess cancer incidence. This case-control study provided detailed information on individual-level covariates and residential history that can be spatially analyzed using generalized additive models (GAMs) and geographical information systems (GIS).</p> <p>Methods</p> <p>We investigated the association between residence and bladder, kidney, and pancreatic cancer on upper Cape Cod. We estimated adjusted odds ratios using GAMs, smoothing on location. A 40-year residential history allowed for latency restrictions. We mapped spatially continuous odds ratios using GIS and identified statistically significant clusters using permutation tests.</p> <p>Results</p> <p>Maps of bladder cancer are essentially flat ignoring latency, but show a statistically significant hot spot near known Massachusetts Military Reservation (MMR) groundwater plumes when 15 years latency is assumed. The kidney cancer map shows significantly increased ORs in the south of the study area and decreased ORs in the north.</p> <p>Conclusion</p> <p>Spatial epidemiology using individual level data from population-based studies addresses many methodological criticisms of cluster studies and generates new exposure hypotheses. Our results provide evidence for spatial clustering of bladder cancer near MMR plumes that suggest further investigation using detailed exposure modeling.</p

Breast cancer risk and drinking water contaminated by wastewater: a case control study

BACKGROUND: Drinking water contaminated by wastewater is a potential source of exposure to mammary carcinogens and endocrine disrupting compounds from commercial products and excreted natural and pharmaceutical hormones. These contaminants are hypothesized to increase breast cancer risk. Cape Cod, Massachusetts, has a history of wastewater contamination in many, but not all, of its public water supplies; and the region has a history of higher breast cancer incidence that is unexplained by the population's age, in-migration, mammography use, or established breast cancer risk factors. We conducted a case-control study to investigate whether exposure to drinking water contaminated by wastewater increases the risk of breast cancer. METHODS: Participants were 824 Cape Cod women diagnosed with breast cancer in 1988–1995 and 745 controls who lived in homes served by public drinking water supplies and never lived in a home served by a Cape Cod private well. We assessed each woman's exposure yearly since 1972 at each of her Cape Cod addresses, using nitrate nitrogen (nitrate-N) levels measured in public wells and pumping volumes for the wells. Nitrate-N is an established wastewater indicator in the region. As an alternative drinking water quality indicator, we calculated the fraction of recharge zones in residential, commercial, and pesticide land use areas. RESULTS: After controlling for established breast cancer risk factors, mammography, and length of residence on Cape Cod, results showed no consistent association between breast cancer and average annual nitrate-N (OR = 1.8; 95% CI 0.6 – 5.0 for ≥ 1.2 vs. < .3 mg/L), the sum of annual nitrate-N concentrations (OR = 0.9; 95% CI 0.6 – 1.5 for ≥ 10 vs. 1 to < 10 mg/L), or the number of years exposed to nitrate-N over 1 mg/L (OR = 0.9; 95% CI 0.5 – 1.5 for ≥ 8 vs. 0 years). Variation in exposure levels was limited, with 99% of women receiving some of their water from supplies with nitrate-N levels in excess of background. The total fraction of residential, commercial, and pesticide use land in recharge zones of public supply wells was associated with a small statistically unstable higher breast cancer incidence (OR = 1.4; 95% CI 0.8–2.4 for highest compared with lowest land use), but risk did not increase for increasing land use fractions. CONCLUSION: Results did not provide evidence of an association between breast cancer and drinking water contaminated by wastewater. The computer mapping methods used in this study to link routine measurements required by the Safe Drinking Water Act with interview data can enhance individual-level epidemiologic studies of multiple health outcomes, including diseases with substantial latency

Spatial analysis of lung, colorectal, and breast cancer on Cape Cod: An application of generalized additive models to case-control data

BACKGROUND: The availability of geographic information from cancer and birth defect registries has increased public demands for investigation of perceived disease clusters. Many neighborhood-level cluster investigations are methodologically problematic, while maps made from registry data often ignore latency and many known risk factors. Population-based case-control and cohort studies provide a stronger foundation for spatial epidemiology because potential confounders and disease latency can be addressed. METHODS: We investigated the association between residence and colorectal, lung, and breast cancer on upper Cape Cod, Massachusetts (USA) using extensive data on covariates and residential history from two case-control studies for 1983–1993. We generated maps using generalized additive models, smoothing on longitude and latitude while adjusting for covariates. The resulting continuous surface estimates disease rates relative to the whole study area. We used permutation tests to examine the overall importance of location in the model and identify areas of increased and decreased risk. RESULTS: Maps of colorectal cancer were relatively flat. Assuming 15 years of latency, lung cancer was significantly elevated just northeast of the Massachusetts Military Reservation, although the result did not hold when we restricted to residences of longest duration. Earlier non-spatial epidemiology had found a weak association between lung cancer and proximity to gun and mortar positions on the reservation. Breast cancer hot spots tended to increase in magnitude as we increased latency and adjusted for covariates, indicating that confounders were partly hiding these areas. Significant breast cancer hot spots were located near known groundwater plumes and the Massachusetts Military Reservation. DISCUSSION: Spatial epidemiology of population-based case-control studies addresses many methodological criticisms of cluster studies and generates new exposure hypotheses. Our results provide evidence for spatial clustering of breast cancer on upper Cape Cod. The analysis suggests further investigation of the potential association between breast cancer and pollution plumes based on detailed exposure modeling

Using video-reflexive ethnography to capture the complexity of leadership enactment in the healthcare workplace

This research was part of LG’s Ph.D. research which was generously funded by NHS Education for Scotland through SMERC.Current theoretical thinking asserts that leadership should be distributed across many levels of healthcare organisations to improve the patient experience and staff morale. However, much healthcare leadership education focusses on the training and competence of individuals and little attention is paid to the interprofessional workplace and how its inherent complexities might contribute to the emergence of leadership. Underpinned by complexity theory, this research aimed to explore how interprofessional healthcare teams enact leadership at a micro-level through influential acts of organising. A whole (interprofessional) team workplace-based study utilising video-reflexive ethnography occurred in two UK clinical sites. Thematic framework analyses of the video data (video-observation and video-reflexivity sessions) were undertaken, followed by in-depth analyses of human–human and human–material interactions. Data analysis revealed a complex interprofessional environment where leadership is a dynamic process, negotiated and renegotiated in various ways throughout interactions (both formal and informal). Being able to “see” themselves at work gave participants the opportunity to discuss and analyse their everyday leadership practices and challenge some of their sometimes deeply entrenched values, beliefs, practices and assumptions about healthcare leadership. These study findings therefore indicate a need to redefine the way that medical and healthcare educators facilitate leadership development and argue for new approaches to research which shifts the focus from leaders to leadership.Publisher PDFPeer reviewe

NF-κB Regulation in T-cells in Pregnancy is Mediated via Fas/FasL Interactions: The Signal for which is Derived from Exosomes Present in Maternal Plasma

Background: Regulated suppression of maternal Th1 immunity is necessary for normal pregnancy since inappropriate Th1 responses results in increased pregnancy loss and complications including intrauterine growth restriction (IUGR). We have shown that suppression of the p65 subunit of NF-κB in maternal T-cells underlies this change in T-cell responses. This study aimed to determine mechanism(s) that control p65 suppression. Methods and findings: Maternal plasma contained particulate factor’s that suppress p65 and induce T-cell apoptosis in Jurkat T-cells and the factor’s was positive for FasL and TRAIL. Both the Fas activating antibody CH11 and recombinant human TRAIL induced Jurkat apoptosis. Specific Fas activation resulted in p65 suppression which was reversed in the presence of the Fas inactivating antibody ZB4. Despite inducing apoptosis, recombinant TRAIL did not suppress p65 expression. Maternal T-cells expressed increased Fas relative to non-pregnant controls. Fas activation in Jurkats resulted in p65 suppression thus limited IL-2 and IFNï § transcription in response to PMA/ionomycin stimulation. In contrast, partial knockdown of Fas in Jurkats prevented suppression of p65 in response to CH11, leading to increased IL-2 and IFNï § production when stimulated with PMA/ionomycin. FasL+ Exosomes isolated from the particulate fraction of maternal plasma specifically induced p65 suppression in Jurkats since suppression was completely reversed with ZB4. In pregnancies complicated with IUGR where Th1 cytokine production is increased, placental expression of FasL was reduced compared to normal controls. Conclusion: Taken together these data suggest that pregnancy derived FasL+ exosomes in maternal plasma regulate p65 levels in circulating T-cells through Fas activation. The expression of Fas on T-cells and FasL on exosomes both dictate the level of p65 suppression and the level of cytokine production in response to stimulation throughout pregnancy. Inappropriate expression of FasL in placental derived exosomes may underlie one mechanism that is abnormal in complications of pregnancy including IUGR