Contractile force is enhanced in Aortas from pendrin null mice due to stimulation of angiotensin II-dependent signaling.

Pendrin is a Cl-/HCO3- exchanger expressed in the apical regions of renal intercalated cells. Following pendrin gene ablation, blood pressure falls, in part, from reduced renal NaCl absorption. We asked if pendrin is expressed in vascular tissue and if the lower blood pressure observed in pendrin null mice is accompanied by reduced vascular reactivity. Thus, the contractile responses to KCl and phenylephrine (PE) were examined in isometrically mounted thoracic aortas from wild-type and pendrin null mice. Although pendrin expression was not detected in the aorta, pendrin gene ablation changed contractile protein abundance and increased the maximal contractile response to PE when normalized to cross sectional area (CSA). However, the contractile sensitivity to this agent was unchanged. The increase in contractile force/cross sectional area observed in pendrin null mice was due to reduced cross sectional area of the aorta and not from increased contractile force per vessel. The pendrin-dependent increase in maximal contractile response was endothelium- and nitric oxide-independent and did not occur from changes in Ca2+ sensitivity or chronic changes in catecholamine production. However, application of 100 nM angiotensin II increased force/CSA more in aortas from pendrin null than from wild type mice. Moreover, angiotensin type 1 receptor inhibitor (candesartan) treatment in vivo eliminated the pendrin-dependent changes contractile protein abundance and changes in the contractile force/cross sectional area in response to PE. In conclusion, pendrin gene ablation increases aorta contractile force per cross sectional area in response to angiotensin II and PE due to stimulation of angiotensin type 1 receptor-dependent signaling. The angiotensin type 1 receptor-dependent increase in vascular reactivity may mitigate the fall in blood pressure observed with pendrin gene ablation

Irregular screening participation increases advanced stage breast cancer at diagnosis:A population-based study

Objective: To evaluate the effect of irregular screening behaviour on the risk of advanced stage breast cancer at diagnosis in Flanders. Methods: All women aged 50–69 who were invited to the organized breast cancer screening and diagnosed with breast cancer before age 72 from 2001 to 2018 were included. All prevalent screen and interval cancers within 2 years of a prevalent screen were excluded. Screening behaviour was categorized based on the number of invitations and performed screenings. Four groups were defined: regular, irregular, only-once, and never attenders. Advanced stage cancer was defined as a stage III + breast cancer. The association between screening regularity and breast cancer stage at diagnosis was evaluated in multivariable logistic regression models, taking age of diagnosis and socio-economic status into account. Results: In total 13.5% of the 38,005 breast cancer cases were diagnosed at the advanced stage. Compared to the regular attenders, the risk of advanced stage breast cancer for the irregular attenders, women who participated only-once, and never attenders was significantly higher with ORadjusted:1.17 (95%CI:1.06–1.29) and ORadjusted:2.18 (95%CI:1.94–2.45), and ORadjusted:5.95 (95%CI:5.33–6.65), respectively. Conclusions: In our study, never attenders were nearly six times more likely to be diagnosed with advanced stage breast cancer than regular attenders, which was much higher than the estimates published thus far. An explanation for this is that the ever screened women is a heterogeneous group regarding the participation profiles which also includes irregular and only-once attenders. The benefit of regular screening should be informed to all women invited for screening

Ethical Issues in the Development of Readiness Cohorts in Alzheimer's Disease Research.

There is growing interest in the development of novel approaches to secondary prevention trials in Alzheimer's disease to facilitate screening and recruitment of research participants and to reduce the time and costs associated with clinical trials. Several international research collaborations are setting up research infrastructures that link existing research cohorts, studies or patient registries to establish 'trial-ready' or 'readiness' cohorts. From these cohorts, individuals are recruited into clinical trial platforms. In setting up such research infrastructures, researchers must make ethically challenging design decisions in at least three areas: re-contacting participants in existing research studies, obtaining informed consent for participation in a readiness cohort, and disclosure of Alzheimer's disease-related biomarkers. These ethical considerations have been examined by a dedicated workgroup within the European Prevention of Alzheimer's Dementia (EPAD) project, a trans-European longitudinal cohort and adaptive proof-of-concept clinical trial platform. This paper offers recommendations for the ethical management of re-contact, informed consent and risk disclosure which may be of value to other research collaborations in the process of developing readiness cohorts for prevention trials in Alzheimer's disease and other disease areas.This work was funded through the Ethical Legal and Social Implications work package of the European Prevention of Alzheimer’s Dementia (EPAD) study EPAD receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115736, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. RM was also funded through the UK National Institute of Health Research grant to the Cambridge Biomedical Research Centre

Machine-learning prediction of cancer survival: a retrospective study using electronic administrative records and a cancer registry

Objectives: Using the prediction of cancer outcome as a model, we have tested the hypothesis that through analysing routinely collected digital data contained in an electronic administrative record (EAR), using machine-learning techniques, we could enhance conventional methods in predicting clinical outcomes. Setting: A regional cancer centre in Australia. Participants: Disease-specific data from a purpose-built cancer registry (Evaluation of Cancer Outcomes (ECO)) from 869 patients were used to predict survival at 6, 12 and 24 months. The model was validated with data from a further 94 patients, and results compared to the assessment of five specialist oncologists. Machine-learning prediction using ECO data was compared with that using EAR and a model combining ECO and EAR data. Primary and secondary outcome measures: Survival prediction accuracy in terms of the area under the receiver operating characteristic curve (AUC). Results: The ECO model yielded AUCs of 0.87 (95% CI 0.848 to 0.890) at 6 months, 0.796 (95% CI 0.774 to 0.823) at 12 months and 0.764 (95% CI 0.737 to 0.789) at 24 months. Each was slightly better than the performance of the clinician panel. The model performed consistently across a range of cancers, including rare cancers. Combining ECO and EAR data yielded better prediction than the ECO-based model (AUCs ranging from 0.757 to 0.997 for 6 months, AUCs from 0.689 to 0.988 for 12 months and AUCs from 0.713 to 0.973 for 24 months). The best prediction was for genitourinary, head and neck, lung, skin, and upper gastrointestinal tumours. Conclusions: Machine learning applied to information from a disease-specific (cancer) database and the EAR can be used to predict clinical outcomes. Importantly, the approach described made use of digital data that is already routinely collected but underexploited by clinical health systems

The effect of accretion temperature on microstructure and bending strength of atmospheric ice

Accurate determination of the mechanical response of atmospheric ice is key to understanding the risks associated with ice impact on aircraft during flight. Two types of atmospheric ice which are of particular interest to the aerospace industry are studied. Rime and Glaze ice are each manufactured in an icing wind tunnel facility under controlled conditions. Rime ice is accreted at a temperature of −20◦C, and Glaze ice is accreted at −5 ◦C. Quasi-static threepoint bend tests are performed on both types of ice to understand the effect of accretion temperature, and therefore microstructure, on strength. The results indicate that the ice accretion temperature, and thus microstructure, has a significant influence on the bending strength. On average, the bending strength of Rime ice is 9.0 ± 0.18 MPa compared to 4.4 ± 0.093 MPa for Glaze. The comparatively lower accretion temperature of Rime results in smaller grain sizes and higher bending strength. In contrast, the effective modulus appears insensitive to ice microstructure, with an average value of 3.5±0.12 GPa for Rime compared to 3.6±0.098 GPa for Glaze. Furthermore, the results indicate that both the bending strength and effective modulus are insensitive to the ice storage time.Innovate UK: 113155 Rolls-Royce pl

Attenuated expression of tenascin-c in ovalbumin-challenged STAT4-/- mice

<p>Abstract</p> <p>Background</p> <p>Asthma leads to structural changes in the airways, including the modification of extracellular matrix proteins such as tenascin-C. The role of tenascin-C is unclear, but it might act as an early initiator of airway wall remodelling, as its expression is increased in the mouse and human airways during allergic inflammation. In this study, we examined whether Th1 or Th2 cells are important regulators of tenascin-C in experimental allergic asthma utilizing mice with impaired Th1 (STAT4-/-) or Th2 (STAT6-/-) immunity.</p> <p>Methods</p> <p>Balb/c wildtype (WT), STAT4-/- and STAT6-/- mice were sensitized with intraperitoneally injected ovalbumin (OVA) followed by OVA or PBS airway challenge. Airway hyperreactivity (AHR) was measured and samples were collected. Real time PCR and immunohistochemistry were used to study cytokines and differences in the expression of tenascin-C. Tenascin-C expression was measured in human fibroblasts after treatment with TNF-α and IFN-γ <it>in vitro</it>.</p> <p>Results</p> <p>OVA-challenged WT mice showed allergic inflammation and AHR in the airways along with increased expression of TNF-α, IFN-γ, IL-4 and tenascin-C in the lungs. OVA-challenged STAT4-/- mice exhibited elevated AHR and pulmonary eosinophilia. The mRNA expression of TNF-α and IFN-γ was low, but the expression of IL-4 was significantly elevated in these mice. OVA-challenged STAT6-/- mice had neither AHR nor pulmonary eosinophilia, but had increased expression of mRNA for TNF-α, IFN-γ and IL-4. The expression of tenascin-C in the lungs of OVA-challenged STAT4-/- mice was weaker than in those of OVA-challenged WT and STAT6-/- mice suggesting that TNF-α and IFN-γ may regulate tenascin-C expression <it>in vivo</it>. The stimulation of human fibroblasts with TNF-α and IFN-γ induced the expression of tenascin-C confirming our <it>in vivo </it>findings.</p> <p>Conclusions</p> <p>Expression of tenascin-C is significantly attenuated in the airways of STAT4-/- mice, which may be due to the impaired secretion of TNF-α and IFN-γ in these mice.</p

Participant Reactions to Two-Way Immersion (TWI) Programs

The purpose of this study was to elicit participant reactions to two-way immersion (TWI) programs in the United States of America. A large number of recent studies have focused on instructor views and perspectives of two-way immersion programs, so this study aimed to gain insight from students who are, or who have, participated in TWI programs throughout North America. One hundred fifty-one TWI schools throughout the United States were contacted and asked to participate in this study. Two similar surveys were developed, one for current TWI students, and another for former TWI students. Students from these two groups were asked to fill out a confidential online survey that addressed specific linguistic skills, abilities, and preferences, as well as connection to the cultures of the target language. Forty-eight percent of the survey respondents were native speakers of English, and the remaining 52% were non-native speakers of English. The number of respondents to the former student survey was so low that the data were inconclusive, and, therefore, will not be included in this study. Since the survey was conducted online, the data were stored in a comma-delimited format for further evaluation. The data were then tallied and analyzed for common themes