NAC and DTT promote TGF-β1 monomer formation: demonstration of competitive binding

TGF-β plays an important role in the genesis and progression of pulmonary fibrosis. We sought to determine the role of mononuclear phagocytes in the activation of TGF-β and found that freshly isolated peripheral blood monocytes spontaneously released TGF-β. Stimulating these monocytes with GM-CSF or LPS, but not MCSF, augmented the activation of TGF-β. In human monocytes, the free thiol compounds DTT and NAC decreased the activity of TGF-β, without affecting TGF-β mRNA transcription. Both NAC and DTT lessened the biological activity of recombinant active TGF-β in a cell-free system. We found that NAC and DTT reduced dimeric active TGF-β from a 25 kDa protein to 12.5 kDa inactive monomer. This conversion was reversed using the oxidizing agent diamide. Diamide also restored biological activity to NAC or DTT-treated TGF-β. Reduction of TGF-β to monomers could competitively inhibit active dimeric TGF-β and block intracellular signaling events. Our observations suggest that modulation of the oxidative state of TGF-β may be a novel therapeutic approach for patients with pulmonary fibrosis

Cellular Origins of EGFR-Driven Lung Cancer Cells Determine Sensitivity to Therapy

Targeting the epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKIs) is one of the major precision medicine treatment options for lung adenocarcinoma. Due to common development of drug resistance to first- and second-generation TKIs, third-generation inhibitors, including osimertinib and rociletinib, have been developed. A model of EGFR-driven lung cancer and a method to develop tumors of distinct epigenetic states through 3D organotypic cultures are described here. It is discovered that activation of the EGFR T790M/L858R mutation in lung epithelial cells can drive lung cancers with alveolar or bronchiolar features, which can originate from alveolar type 2 (AT2) cells or bronchioalveolar stem cells, but not basal cells or club cells of the trachea. It is also demonstrated that these clones are able to retain their epigenetic differences through passaging orthotopically in mice and crucially that they have distinct drug vulnerabilities. This work serves as a blueprint for exploring how epigenetics can be used to stratify patients for precision medicine decisions

SMA CO(J=6-5) and 435 micron interferometric imaging of the nuclear region of Arp 220

We have used the Submillimeter Array (SMA) to make the first interferometric observations (beam size ~1") of the 12CO J=6-5 line and 435 micron (690 GHz) continuum emission toward the central region of the nearby ULIRG Arp 220. These observations resolve the eastern and western nuclei from each other, in both the molecular line and dust continuum emission. At 435 micron, the peak intensity of the western nucleus is stronger than the eastern nucleus, and the difference in peak intensities is less than at longer wavelengths. Fitting a simple model to the dust emission observed between 1.3 mm and 435 micron suggests that dust emissivity power law index in the western nucleus is near unity and steeper in the eastern nucleus, about 2, and that the dust emission is optically thick at the shorter wavelength. Comparison with single dish measurements indicate that the interferometer observations are missing ~60% of the dust emission, most likely from a spatially extended component to which these observations are not sensitive. The 12CO J=6-5 line observations clearly resolve kinematically the two nuclei. The distribution and kinematics of the 12CO J=6-5 line appear to be very similar to lower J CO lies observed at similar resolution. Analysis of multiple 12CO line intensities indicates that the molecular gas in both nuclei have similar excitation conditions, although the western nucleus is warmer and denser. The excitation conditions are similar to those found in other extreme environments, including M82, Mrk 231, and BR 1202-0725. Simultaneous lower resolution observations of the 12CO, 13CO, and C18O J=2-1 lines show that the 13CO and C18O lines have similar intensities, which suggests that both of these lines are optically thick, or possibly that extreme high mass star formation has produced in an overabundance of C18O.Comment: 13 pages (emulateapj), 10 figures, Accepted for publication in Ap

Evaluation of community-level interventions to increase early initiation of antenatal care in pregnancy: protocol for the Community REACH study, a cluster randomised controlled trial with integrated process and economic evaluations

BACKGROUND: The provision of high-quality maternity services is a priority for reducing inequalities in health outcomes for mothers and infants. Best practice includes women having their initial antenatal appointment within the first trimester of pregnancy in order to provide screening and support for healthy lifestyles, well-being and self-care in pregnancy. Previous research has identified inequalities in access to antenatal care, yet there is little evidence on interventions to improve early initiation of antenatal care. The Community REACH trial will assess the effectiveness and cost-effectiveness of engaging communities in the co-production and delivery of an intervention that addresses this issue. METHODS/DESIGN: The study design is a matched cluster randomised controlled trial with integrated process and economic evaluations. The unit of randomisation is electoral ward. The intervention will be delivered in 10 wards; 10 comparator wards will have normal practice. The primary outcome is the proportion of pregnant women attending their antenatal booking appointment by the 12th completed week of pregnancy. This and a number of secondary outcomes will be assessed for cohorts of women (n = approximately 1450 per arm) who give birth 2-7 and 8-13 months after intervention delivery completion in the included wards, using routinely collected maternity data. Eight hospitals commissioned to provide maternity services in six NHS trusts in north and east London and Essex have been recruited to the study. These trusts will provide anonymised routine data for randomisation and outcomes analysis. The process evaluation will examine intervention implementation, acceptability, reach and possible causal pathways. The economic evaluation will use a cost-consequences analysis and decision model to evaluate the intervention. Targeted community engagement in the research process was a priority. DISCUSSION: Community REACH aims to increase early initiation of antenatal care using an intervention that is co-produced and delivered by local communities. This pragmatic cluster randomised controlled trial, with integrated process and economic evaluation, aims to rigorously assess the effectiveness of this public health intervention, which is particularly complex due to the required combination of standardisation with local flexibility. It will also answer questions about scalability and generalisability. TRIAL REGISTRATION: ISRCTN registry: registration number 63066975 . Registered on 18 August 2015

Contributions of high- and low-quality patches to a metapopulation with stochastic disturbance

© The Author(s), 2010. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Theoretical Ecology 5 (2012): 167-179, doi:10.1007/s12080-010-0106-9.Studies of time-invariant matrix metapopulation models indicate that metapopulation growth rate is usually more sensitive to the vital rates of individuals in high-quality (i.e., good) patches than in low-quality (i.e., bad) patches. This suggests that, given a choice, management efforts should focus on good rather than bad patches. Here, we examine the sensitivity of metapopulation growth rate for a two-patch matrix metapopulation model with and without stochastic disturbance and found cases where managers can more efficiently increase metapopulation growth rate by focusing efforts on the bad patch. In our model, net reproductive rate differs between the two patches so that in the absence of dispersal, one patch is high quality and the other low quality. Disturbance, when present, reduces net reproductive rate with equal frequency and intensity in both patches. The stochastic disturbance model gives qualitatively similar results to the deterministic model. In most cases, metapopulation growth rate was elastic to changes in net reproductive rate of individuals in the good patch than the bad patch. However, when the majority of individuals are located in the bad patch, metapopulation growth rate can be most elastic to net reproductive rate in the bad patch. We expand the model to include two stages and parameterize the patches using data for the softshell clam, Mya arenaria. With a two-stage demographic model, the elasticities of metapopulation growth rate to parameters in the bad patch increase, while elasticities to the same parameters in the good patch decrease. Metapopulation growth rate is most elastic to adult survival in the population of the good patch for all scenarios we examine. If the majority of the metapopulation is located in the bad patch, the elasticity to parameters of that population increase but do not surpass elasticity to parameters in the good patch. This model can be expanded to include additional patches, multiple stages, stochastic dispersal, and complex demography.Financial support was provided by the Woods Hole Oceanographic Institution Academic Programs Office; National Science Foundation grants OCE-0326734, OCE- 0215905, OCE-0349177, DEB-0235692, DEB-0816514, DMS- 0532378, OCE-1031256, and ATM-0428122; and by National Oceanic and Atmospheric Administration National Sea Grant College Program Office, Department of Commerce, under Grant No. NA86RG0075 (Woods Hole Oceanographic Institution Sea Grant Project No. R/0-32), and Grant No. NA16RG2273 (Woods Hole Oceanographic Institution Sea Grant Project No. R/0-35)

A call for action to establish a research agenda for building a future health workforce in Europe

This Call for Action is closely linked to the European Public Health Association (EUPHA) and its new section ‘Health Workforce Research’. The idea was first developed during a pre-conference and two workshops at the EUPHA Conference in November 2016 in Vienna and further investigated at the EUPHA Conference in November 2017. We wish to thank all participants for inspiring discussions and for sharing ideas and knowledge.Peer reviewedPublisher PD

Patents and Industrialisation. An Historical Overview of the British Case, 1624-1907

A Report to the Strategic Advisory Board on Intellectual Property Policy (SABIP), U

Essential Content for Teaching Implementation Practice in Healthcare: A Mixed-Methods Study of Teams Offering Capacity-Building Initiatives

Background Applying the knowledge gained through implementation science can support the uptake of research evidence into practice; however, those doing and supporting implementation (implementation practitioners) may face barriers to applying implementation science in their work. One strategy to enhance individuals’ and teams’ ability to apply implementation science in practice is through training and professional development opportunities (capacity-building initiatives). Although there is an increasing demand for and offerings of implementation practice capacity-building initiatives, there is no universal agreement on what content should be included. In this study we aimed to explore what capacity-building developers and deliverers identify as essential training content for teaching implementation practice. Methods We conducted a convergent mixed-methods study with participants who had developed and/or delivered a capacity-building initiative focused on teaching implementation practice. Participants completed an online questionnaire to provide details on their capacity-building initiatives; took part in an interview or focus group to explore their questionnaire responses in depth; and offered course materials for review. We analyzed a subset of data that focused on the capacity-building initiatives’ content and curriculum. We used descriptive statistics for quantitative data and conventional content analysis for qualitative data, with the data sets merged during the analytic phase. We presented frequency counts for each category to highlight commonalities and differences across capacity-building initiatives. Results Thirty-three individuals representing 20 capacity-building initiatives participated. Study participants identified several core content areas included in their capacity-building initiatives: (1) taking a process approach to implementation; (2) identifying and applying implementation theories, models, frameworks, and approaches; (3) learning implementation steps and skills; (4) developing relational skills. In addition, study participants described offering applied and pragmatic content (e.g., tools and resources), and tailoring and evolving the capacity-building initiative content to address emerging trends in implementation science. Study participants highlighted some challenges learners face when acquiring and applying implementation practice knowledge and skills. Conclusions This study synthesized what experienced capacity-building initiative developers and deliverers identify as essential content for teaching implementation practice. These findings can inform the development, refinement, and delivery of capacity-building initiatives, as well as future research directions, to enhance the translation of implementation science into practice

"I do what I have to do to survive": An investigation into the perceptions, experiences and economic considerations of women engaged in sex work in Northern Namibia

<p>Abstract</p> <p>Background</p> <p>There is little published research investigating sex work in Namibia, particularly in rural areas. Therefore, the aim of this paper was to determine the views of women engaged in sex work in the Oshakati area of Namibia concerning the main factors influencing their use, or non-use, of male condoms during transactional sexual exchanges.</p> <p>Methods</p> <p>Qualitative interviews were used to better understand the perceptions, experiences and economic considerations of female sex workers in Namibia who were involved in a Behavior Change Communication Program encouraging safer sex practices among high-risk populations in 2006 and 2007.</p> <p>Results</p> <p>While the Behavior Change Communication Program has made significant strides in educating and empowering young women to negotiate more consistent condom use with sexual partners, the gendered economic inequalities and power imbalances within rural and semi-urban Namibian society that favor men hinder further advancement towards positive behavioral change for HIV prevention and also hinder the development of the loving relationships sought by some sex workers.</p> <p>Conclusion</p> <p>This study found that sex workers and transactional sex encounters are heterogeneous entities dependent upon the characteristics of the man (known, stranger, wealthy, attractive to the woman) and the woman (in financial need, desiring love). These features all influence condom use. The 3 E's 'education, empowerment and economic independence' are critical factors needed to encourage and facilitate consistent condom use to prevent HIV transmission. Without financial independence and occupational alternatives building on their health education and empowerment, women who engage in sex work-and transactional sex more generally-will remain largely marginalized from Namibian society, and will continue engaging in risky sexual practices that facilitate HIV acquisition and transmission throughout the community.</p

Physical Activity, Heart Rate, Metabolic Profile, and Estradiol in Premenopausal Women

Purpose: To study whether physical inactive women with a tendency to develop metabolic syndrome have high levels of 17[beta]-estradiol (E2) of importance for breast cancer risk. Methods: Two hundred and four healthy women of reproductive age were assessed for self-reported leisure-time physical activity (LPA), resting heart rate (HR), blood pressure (BP), anthropometry, and serum glucose, lipids, and insulin [Norwegian Energy Balance and Breast Cancer Aspect (EBBA) study]. E2 was measured in daily saliva samples throughout an entire menstrual cycle. A clustered metabolic risk score [z metabolic syndrome (zMS); total cholesterol-high-density lipoprotein-cholesterol (HDL-C) ratio, insulin resistance, total fat tissue, BP, and triglycerides] was defined. Linear regression and linear mixed models were used, and confounding factors were tested. Results: Physically active women had lower fat percentage (Ptrend = 0.003) and HRs (Ptrend = 0.003) than sedentary women. We estimated an increase in E2 of 1.27 pmol[middle dot]L-1 [95% confidence interval (CI), 0.06-2.47] for each 11.7 beats[middle dot]min-1 (1 SD) increase in HR, and this corresponds to the 7% change in mean concentration of E2 for the total group. Associations with E2 were also found for fat tissue, total cholesterol-HDL-C ratio, insulin resistance, and triglycerides. A dose-response relationship was observed among the three levels of LPA and HR and zMS (Ptrend = 0.03 for LPA; Ptrend = 0.004 for HR). Women in the highest tertile of the clustered metabolic risk score had average salivary E2profiles that were markedly higher, throughout the cycle, than those of the other groups, with a cycle peak-day difference in E2 of 22-28%. Conclusion: LPA and HR were associated with metabolic risk score, and this score was associated with daily level of E2, pointing to important biologic mechanisms operating between a sedentary lifestyle and an increased breast cancer risk.AnthropologyHuman Evolutionary Biolog