Presidential influence over the systemic agenda

Abstract One of the most widely accepted sources of presidential power is agenda setting. Being able to affect the media's agenda on key issues-influencing the systemic agenda and "expanding the scope of conflict"-has enormous consequences for the president's ability to govern effectively. Yet the literature to date has not conclusively determined the extent to which presidents consistently set agendas, especially over the media, because it has not explicitly considered variation in agenda-setting influence by policy type. For these reasons, we test whether presidential public statements have increased the media's attention to three policy areas. Using Vector Autoregression (VAR) analysis, we demonstrate that presidents have some influence over the systemic agenda, at least in the short term, with policy type being an important predictor of presidential influence. Understanding when and why presidents may or may not be successful agenda setters is crucial to explaining the varying legislative impacts of presidential speech making. Agenda setting has long been viewed as a vital source of power in American politics. Whoever controls the agenda affects which issues are debated, how they are framed, and who may participate. Much work on agenda setting holds unequivocally that presidents have this power, and that they are uniquely situated to affect the national agenda. John Kingdon (1984, 25), in his seminal study on Washington agenda setting, maintained that "no other single actor in the political system has quite the capability of the president to set agendas." Baumgartner and Jones (1993, 241) surmised, "no single actor can focus attention as clearly, or change the motivations of such a great number of other actors, as the president." After all, these scholars assert that Congress, the public, and the news media regularly look to presidents for leadership on the nation's most pressing issues. Presidential influence over agenda setting arguably increases the president's ability to govern effectively. If the president dictates the issues that Congress debates each legislative session, he is more likely to succeed on his top legislative prioritie

Incidence of second and higher order smoking-related primary cancers following lung cancer: a population-based cohort study

Background Lung cancer five-year survival has doubled over fifteen years. Although the risk of second primary cancer is recognised, quantification over time is lacking. We describe the incidence of second and higher order smoking-related primary cancers in lung cancer survivors, identifying high-incidence groups and how incidence changes over time from first diagnosis. Methods Data on smoking-related primary cancers (lung, laryngeal, head and neck, oesophageal squamous carcinoma and bladder) diagnosed in England between 2000-2014 was obtained from Public Health England National Cancer Registration and Analysis Service. We calculated absolute incidence rates and standardised incidence rate ratios, both overall and for various sub-groups of second primary cancer for up to 10 years from initial diagnosis of lung cancer, using Poisson regression. Results Elevated incidence of smoking-related second primary cancer persists for at least ten years from first lung cancer diagnosis with those aged 50 and 79 at first diagnosis at particularly high risk. The most frequent type of second malignancy was lung cancer although the highest standardised incidence rate ratios were for oesophageal squamous carcinoma (2.4) and laryngeal cancers (2.8) and consistently higher in women than in men. Over the last decade the incidence of second primary lung cancer has doubled. Conclusion Lung cancer survivors have increased incidence of subsequent lung, laryngeal, head and neck and oesophageal squamous cell carcinoma for at least a decade from first diagnosis. Consideration should be given to increasing routine follow-up from 5 years to 10 years for those at highest risk, alongside surveillance for other smoking-related cancers.This study was supported the Early Diagnosis programme Cancer Research UK Cambridge Centre. FMW is supported by an NIHR Clinician Scientist award. GL is supported by a Cancer Research UK award (Advanced Clinician Scientist Fellowship C18081/A18180). RCR is part funded by the Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre

Development and Characterisation of a Human Chronic Skin Wound Cell Line:Towards an Alternative for Animal Experimentation

Background: Chronic skin wounds are a growing financial burden for healthcare providers, causing discomfort/immobility to patients. Whilst animal chronic wound models have been developed to allow for mechanistic studies and to develop/test potential therapies, such systems are not good representations of the human chronic wound state. As an alternative, human chronic wound fibroblasts (CWFs) have permitted an insight into the dysfunctional cellular mechanisms that are associated with these wounds. However, such cells strains have a limited replicative lifespan and therefore a limited reproducibility/usefulness. Objectives: To develop/characterise immortalised cell lines of CWF and patient-matched normal fibroblasts (NFs). Methods and Results: Immortalisation with human telomerase resulted in both CWF and NF proliferating well beyond their replicative senescence end-point (respective cell strains senesced as normal). Gene expression analysis demonstrated that, whilst proliferation-associated genes were up-regulated in the cell lines (as would be expected), the immortalisation process did not significantly affect the disease-specific genotype. Immortalised CWF (as compared to NF) also retained a distinct impairment in their wound repopulation potential (in line with CWF cell strains). Conclusions: These novel CWF cell lines are a credible animal alternative and could be a valuable research tool for understanding both the aetiology of chronic skin wounds and for therapeutic pre-screening

Un "simposio di sapienza e affetto"

Muscle hypertrophy occurs following increased protein synthesis, which requires activation of the ribosomal complex. Additionally, increased translational capacity via elevated ribosomal RNA (rRNA) synthesis has also been implicated in resistance training-induced skeletal muscle hypertrophy. The time course of ribosome biogenesis following resistance exercise (RE) and the impact exerted by differing recovery strategies remains unknown. In the present study, the activation of transcriptional regulators, the expression levels of pre-rRNA, and mature rRNA components were measured through 48 h after a single-bout RE. In addition, the effects of either low-intensity cycling (active recovery, ACT) or a cold-water immersion (CWI) recovery strategy were compared. Nine male subjects performed two bouts of high-load RE randomized to be followed by 10 min of either ACT or CWI. Muscle biopsies were collected before RE and at 2, 24, and 48 h after RE. RE increased the phosphorylation of the p38-MNK1-eIF4E axis, an effect only evident with ACT recovery. Downstream, cyclin D1 protein, total eIF4E, upstream binding factor 1 (UBF1), and c-Myc proteins were all increased only after RE with ACT. This corresponded with elevated abundance of the pre-rRNAs (45S, ITS-28S, ITS-5.8S, and ETS-18S) from 24 h after RE with ACT. In conclusion, coordinated upstream signaling and activation of transcriptional factors stimulated pre-rRNA expression after RE. CWI, as a recovery strategy, markedly blunted these events, suggesting that suppressed ribosome biogenesis may be one factor contributing to the impaired hypertrophic response observed when CWI is used regularly after exercise

Acute impact of conventional and eccentric cycling on platelet and vascular function in patients with chronic heart failure.

Evidence-based guidelines recommend exercise therapy for patients with chronic heart failure (CHF). Such patients have increased atherothrombotic risk. Exercise can transiently increase platelet activation and reactivity and decrease vascular function in healthy participants, although data in CHF is scant. Eccentric (ECC) cycling is a novel exercise modality which may be particularly suited to patients with CHF, but the acute impacts of ECC on platelet and vascular function are currently unknown. Our null hypothesis was that ECC and concentric (CON) cycling, performed at matched external workloads, would not induce changes in platelet or vascular function in patients with CHF. Eleven patients with heart failure with reduced ejection fraction (HFrEF) took part in discrete bouts of ECC and CON cycling. Before and immediately after exercise, vascular function was assessed by measuring diameter and flow mediated dilation (FMD) of the brachial artery. Platelet function was measured by the flow cytometric determination of glycoprotein IIb/IIIa activation and granule exocytosis in the presence and absence of platelet agonists. ECC increased baseline artery diameter (pre: 4.0±0.8mm vs post: 4.2±0.7mm, P=0.04) and decreased FMD%. When changes in baseline artery diameter were accounted for the decrease in FMD post-ECC was no longer significant. No changes were apparent after CON. Neither ECC nor CON resulted in changes to any platelet function measures (all P>0.05). These results suggest both ECC and CON cycling at a moderate intensity and short duration can be performed by patients with HFrEF, without detrimental impacts on vascular or platelet function

30-day mortality after systemic anticancer treatment for breast and lung cancer in England: a population-based, observational study

Background: 30-day mortality might be a useful indicator of avoidable harm to patients from systemic anticancer treatments, but data for this indicator are limited. The Systemic Anti-Cancer Therapy (SACT) dataset collated by Public Health England allows the assessment of factors affecting 30-day mortality in a national patient population. The aim of this first study based on the SACT dataset was to establish national 30-day mortality benchmarks for breast and lung cancer patients receiving SACT in England, and to start to identify where patient care could be improved. Methods: In this population-based study, we included all women with breast cancer and all men and women with lung cancer residing in England, who were 24 years or older and who started a cycle of SACT in 2014 irrespective of the number of previous treatment cycles or programmes, and irrespective of their position within the disease trajectory. We calculated 30-day mortality after the most recent cycle of SACT for those patients. We did logistic regression analyses, adjusting for relevant factors, to examine whether patient, tumour, or treatment-related factors were associated with the risk of 30-day mortality. For each cancer type and intent, we calculated 30-day mortality rates and patient volume at the hospital trust level, and contrasted these in a funnel plot. Findings: Between Jan 1, and Dec, 31, 2014, we included 23 228 patients with breast cancer and 9634 patients with non-small cell lung cancer (NSCLC) in our regression and trust-level analyses. 30-day mortality increased with age for both patients with breast cancer and patients with NSCLC treated with curative intent, and decreased with age for patients receiving palliative SACT (breast curative: odds ratio [OR] 1·085, 99% CI 1·040–1·132; p<0·0001; NSCLC curative: 1·045, 1·013–1·079; p=0·00033; breast palliative: 0·987, 0·977–0·996; p=0·00034; NSCLC palliative: 0·987, 0·976–0·998; p=0·0015). 30-day mortality was also significantly higher for patients receiving their first reported curative or palliative SACT versus those who received SACT previously (breast palliative: OR 2·326 99% CI 1·634–3·312; p<0·0001; NSCLC curative: 3·371, 1·554–7·316; p<0·0001; NSCLC palliative: 2·667, 2·109–3·373; p<0·0001), and for patients with worse general wellbeing (performance status 2–4) versus those who were generally well (breast curative: 6·057, 1·333–27·513; p=0·0021; breast palliative: 6·241, 4·180–9·319; p<0·0001; NSCLC palliative: 3·384, 2·276–5·032; p<0·0001). We identified trusts with mortality rates in excess of the 95% control limits; this included seven for curative breast cancer, four for palliative breast cancer, five for curative NSCLC, and seven for palliative NSCLC. Interpretation: Our findings show that several factors affect the risk of early mortality of breast and lung cancer patients in England and that some groups are at a substantially increased risk of 30-day mortality. The identification of hospitals with significantly higher 30-day mortality rates should promote review of clinical decision making in these hospitals. Furthermore, our results highlight the importance of collecting routine data beyond clinical trials to better understand the factors placing patients at higher risk of 30-day mortality, and ultimately improve clinical decision making. Our insights into the factors affecting risk of 30-day mortality will help treating clinicians and their patients predict the balance of harms and benefits associated with SACT. Funding: Public Health England

Sequential screening for lung cancer in a high-risk group: randomised controlled trial: LungSEARCH: a randomised controlled trial of Surveillance using sputum and imaging for the EARly detection of lung Cancer in a High-risk group.

BACKGROUND: Low-dose computed tomography (LDCT) screening detects early-stage lung cancer and reduces mortality. We proposed a sequential approach targeted to a high-risk group as a potentially efficient screening strategy. METHODS: LungSEARCH was a national multicentre randomised trial. Current/ex-smokers with mild/moderate chronic obstructive pulmonary disease (COPD) were allocated (1:1) to have 5 years surveillance or not. Screened participants provided annual sputum samples for cytology and cytometry, and if abnormal were offered annual LDCT and autofluorescence bronchoscopy (AFB). Those with normal sputum provided annual samples. The primary end-point was the percentage of lung cancers diagnosed at stage I/II (nonsmall cell) or limited disease (small cell). RESULTS: 1568 participants were randomised during 2007-2011 from 10 UK centres. 85.2% of those screened provided an adequate baseline sputum sample. There were 42 lung cancers among 785 screened individuals and 36 lung cancers among 783 controls. 54.8% (23 out of 42) of screened individuals versus 45.2% (14 out of 31) of controls with known staging were diagnosed with early-stage disease (one-sided p=0.24). Relative risk was 1.21 (95% CI 0.75-1.95) or 0.82 (95% CI 0.52-1.31) for early-stage or advanced cancers, respectively. Overall sensitivity for sputum (in those randomised to surveillance) was low (40.5%) with a cumulative false-positive rate (FPR) of 32.8%. 55% of cancers had normal sputum results throughout. Among sputum-positive individuals who had AFB, sensitivity was 45.5% and cumulative FPR was 39.5%; the corresponding measures for those who had LDCT were 100% and 16.1%, respectively. CONCLUSIONS: Our sequential strategy, using sputum cytology/cytometry to select high-risk individuals for AFB and LDCT, did not lead to a clear stage shift and did not improve the efficiency of lung cancer screening

Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells

Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cell–dependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5; ERK; PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10– and IL-21–mediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21–induced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic difference in the mechanism underlying differentiation of naive versus memory B cells.This work was funded by project and program grants from the National Health and Medical Research Council (NHMRC) of Australia (to E.K. Deenick, C.S. Ma, D.A. Fulcher, M.C. Cook, and S.G. Tangye) and the Rockefeller University Center for 541 Clinical and Translational science (5UL1RR024143 to J.L. Casanova). C.S. Ma is a recipient of a Career Development Fellowship, L.J. Berglund is a recipient of a Medical Postgraduate Scholarship, and S.G. Tangye is a recipient of a Principal Research Fellowship from the NHMRC of Australia. L. Moens is the recipient of a Postdoctoral Fellowship from the Research Foundation-Flanders (FWO), Belgium

Role of enzymic antioxidants in mediating oxidative stress and contrasting wound healing capabilities in oral mucosal/skin fibroblasts and tissues

Unlike skin, oral mucosal wounds are characterized by rapid healing and minimal scarring, attributable to the “enhanced” healing properties of oral mucosal fibroblasts (OMFs). As oxidative stress is increasingly implicated in regulating wound healing outcomes, this study compared oxidative stress biomarker and enzymic antioxidant profiles between patient-matched oral mucosal/skin tissues and OMFs/skin fibroblasts (SFs) to determine whether superior oral mucosal antioxidant capabilities and reduced oxidative stress contributed to these preferential healing properties. Oral mucosa and skin exhibited similar patterns of oxidative protein damage and lipid peroxidation, localized within the lamina propria/dermis and oral/skin epithelia, respectively. SOD1, SOD2, SOD3 and catalase were primarily localized within epithelial tissues overall. However, SOD3 was also widespread within the lamina propria localized to OMFs, vasculature and the extracellular matrix. OMFs were further identified as being more resistant to reactive oxygen species (ROS) generation and oxidative DNA/protein damage than SFs. Despite histological evaluation suggesting that oral mucosa possessed higher SOD3 expression, this was not fully substantiated for all OMFs examined due to inter-patient donor variability. Such findings suggest that enzymic antioxidants have limited roles in mediating privileged wound healing responses in OMFs, implying that other non-enzymic antioxidants could be involved in protecting OMFs from oxidative stress overall

Implementation of multimodal computed tomography in a telestroke network : five-year experience

Aims: Penumbral selection is best-evidence practice for thrombectomy in the 6-24 hour window. Moreover, it helps to identify the best responders to thrombolysis. Multimodal computed tomography (mCT) at the primary centre—including noncontrast CT, CT perfusion, and CT angiography—may enhance reperfusion therapy decision-making. We developed a network with five spoke primary stroke sites and assessed safety, feasibility, and influence of mCT in rural hospitals on decision-making for thrombolysis. Methods: Consecutive patients assessed via telemedicine from April 2013 to June 2018. Clinical outcomes were measured, and decision-making compared using theoretical models for reperfusion therapy applied without mCT guidance. Symptomatic intracranial hemorrhage (sICH) was assessed according to Safe Implementation of Treatments in Stroke Thrombolysis Registry criteria. Results: A total of 334 patients were assessed, 240 received mCT, 58 were thrombolysed (24.2%). The mean age of thrombolysed patients was 70 years, median baseline National Institutes of Health Stroke Scale was 10 (IQR 7-18) and 23 (39.7%) had a large vessel occlusion. 1.7% had sICH and 3.5% parenchymal hematoma. Three months poststroke, 55% were independent, compared with 70% in the non-thrombolysed group. Conclusion: Implementation of CTP in rural centers was feasible and led to high thrombolysis rates with low rates of sICH. © 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd