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The benefit of CT coronary angiography (CTCA) in patients presenting with stable chest pain has not been systematically studied. We aimed to assess the effect of CTCA on the diagnosis, management, and outcome of patients referred to the cardiology clinic with suspected angina due to coronary heart disease. In this prospective open-label, parallel-group, multicentre trial, we recruited patients aged 18–75 years referred for the assessment of suspected angina due to coronary heart disease from 12 cardiology chest pain clinics across Scotland. We randomly assigned (1:1) participants to standard care plus CTCA or standard care alone. Randomisation was done with a web-based service to ensure allocation concealment. The primary endpoint was certainty of the diagnosis of angina secondary to coronary heart disease at 6 weeks. All analyses were intention to treat, and patients were analysed in the group they were allocated to, irrespective of compliance with scanning. This study is registered with ClinicalTrials.gov, number NCT01149590. Between Nov 18, 2010, and Sept 24, 2014, we randomly assigned 4146 (42%) of 9849 patients who had been referred for assessment of suspected angina due to coronary heart disease. 47% of participants had a baseline clinic diagnosis of coronary heart disease and 36% had angina due to coronary heart disease. At 6 weeks, CTCA reclassified the diagnosis of coronary heart disease in 558 (27%) patients and the diagnosis of angina due to coronary heart disease in 481 (23%) patients (standard care 22 [1%] and 23 [1%]; p<0·0001). Although both the certainty (relative risk [RR] 2·56, 95% CI 2·33–2·79; p<0·0001) and frequency of coronary heart disease increased (1·09, 1·02–1·17; p=0·0172), the certainty increased (1·79, 1·62–1·96; p<0·0001) and frequency seemed to decrease (0·93, 0·85–1·02; p=0·1289) for the diagnosis of angina due to coronary heart disease. This changed planned investigations (15% vs 1%; p<0·0001) and treatments (23% vs 5%; p<0·0001) but did not affect 6-week symptom severity or subsequent admittances to hospital for chest pain. After 1·7 years, CTCA was associated with a 38% reduction in fatal and non-fatal myocardial infarction (26 vs 42, HR 0·62, 95% CI 0·38–1·01; p=0·0527), but this was not significant. In patients with suspected angina due to coronary heart disease, CTCA clarifies the diagnosis, enables targeting of interventions, and might reduce the future risk of myocardial infarction. The Chief Scientist Office of the Scottish Government Health and Social Care Directorates funded the trial with supplementary awards from Edinburgh and Lothian's Health Foundation Trust and the Heart Diseases Research Fund.

The Scottish Computed Tomography of the Heart (SCOT-HEART) trial demonstrated that management guided by coronary CT angiography (CCTA) improved the diagnosis, management, and outcome of patients with stable chest pain. We aimed to assess whether CCTA-guided care results in sustained long-term improvements in management and outcomes. SCOT-HEART was an open-label, multicentre, parallel group trial for which patients were recruited from 12 outpatient cardiology chest pain clinics across Scotland. Eligible patients were aged 18–75 years with symptoms of suspected stable angina due to coronary heart disease. Patients were randomly assigned (1:1) to standard of care plus CCTA or standard of care alone. In this prespecified 10-year analysis, prescribing data, coronary procedural interventions, and clinical outcomes were obtained through record linkage from national registries. The primary outcome was coronary heart disease death or non-fatal myocardial infarction on an intention-to-treat basis. This trial is registered at ClinicalTrials.gov (NCT01149590) and is complete. Between Nov 18, 2010, and Sept 24, 2014, 4146 patients were recruited (mean age 57 years [SD 10], 2325 [56·1%] male, 1821 [43·9%] female), with 2073 randomly assigned to standard care and CCTA and 2073 to standard care alone. After a median of 10·0 years (IQR 9·3–11·0), coronary heart disease death or non-fatal myocardial infarction was less frequent in the CCTA group compared with the standard care group (137 [6·6%] vs 171 [8·2%]; hazard ratio [HR] 0·79 [95% CI 0·63–0·99], p=0·044). Rates of all-cause, cardiovascular, and coronary heart disease death, and non-fatal stroke, were similar between the groups (p>0·05 for all), but non-fatal myocardial infarctions (90 [4·3%] vs 124 [6·0%]; HR 0·72 [0·55–0·94], p=0·017) and major adverse cardiovascular events (172 [8·3%] vs 214 [10·3%]; HR 0·80 [0·65–0·97], p=0·026) were less frequent in the CCTA group. Rates of coronary revascularisation procedures were similar (315 [15·2%] vs 318 [15·3%]; HR 1·00 [0·86–1·17], p=0·99) but preventive therapy prescribing remained more frequent in the CCTA group (831 [55·9%] of 1486 vs 728 [49·0%] of 1485 patients with available data; odds ratio 1·17 [95% CI 1·01–1·36], p=0·034). After 10 years, CCTA-guided management of patients with stable chest pain was associated with a sustained reduction in coronary heart disease death or non-fatal myocardial infarction. Identification of coronary atherosclerosis by CCTA improves long-term cardiovascular disease prevention in patients with stable chest pain. The Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Edinburgh and Lothian's Health Foundation Trust, British Heart Foundation, and Heart Diseases Research Fund.

An informal review of literature on exercise and cancer was undertaken in order to examine the role of exercise in cancer prevention, treatment, rehabilitation, and late survivorship. Population-wide studies show that cancer incidence decreases with increasing physical activity levels. Exercise can decrease the side effects of anticancer therapy, and can aid in recovery and rehabilitation following chemotherapy, radiation, and surgery. Observational studies of breast, colon, and prostate cancer survivors show robust associations between post-diagnosis exercise and decreased cancer-specific mortality. In addition, all-cause mortality in cancer survivors decreases with increasing amounts of exercise. The amount and intensity of exercise required to measure a survival benefit appear to vary by primary tumor type. Decreased breast cancer mortality is seen with the equivalent of 3 hours of walking per week, and decreased colon cancer mortality with 6 hours of walking per week. For these tumors, more vigorous exercise may not improve survival. However, after a prostate cancer diagnosis, more intense exercise is associated with superior survival when compared with walking. The mechanisms behind these differences remain to be elucidated. Further research is also needed to determine the various amounts and intensities of exercise required for optimum cancer prevention, recovery, and survival.

Purpose To determine the histological distribution and trends in incidence of sinonasal malignancies in Jamaica. Methods Cases of all sinonasal malignancies diagnosed between 1973 and 2007 were extracted from the archives of the Jamaica Cancer Registry. Data recorded for each case included age at diagnosis, sex, year of diagnosis, topography, and histology. Data were used to calculate frequencies, age-specific incidence rates, and age-standardized incidence rates (ASRs). Linear regression analysis was used to determine significance of trends in incidence rates; p values of ≤0.05 were significant. Results Sinonasal malignancies were commoner in males (male: female ratio, 1.1:1), and the median ages were 62 (males) and 66 years (females). Most were located in either the maxillary sinus (61.3%) or nasal cavity (24.3%). The commonest histological types were squamous cell carcinoma (SCC) (55.9%) and non-Hodgkin’s lymphoma (17.1%), which were predominantly of T-cell immunophenotype, in both the nasal cavity and sinuses. There was no documentation in registry data regarding separation into NK/T and peripheral T-subtypes. The ASRs in males and females were consistently less than 1.5 per 100,000 per year. In males, there was a significant decrease in SCC ASR ( p  = 0.014) over time. Conclusions The age, gender, and anatomical and histological distribution patterns of sinonasal malignancies in Jamaica are similar to those reported internationally, and the low ASRs are in keeping with previous global reports. Broader local immunohistochemistry panels are warranted for further delineation of sinonasal T-cell lymphomas. Investigation into factors contributing to the decreasing incidence of sinonasal SCC is also required.

The obligate intracellular protozoan parasite Leishmania binds several host cell receptors to trigger its uptake by phagocytic cells, ultimately resulting in visceral or cutaneous leishmaniasis. After Leishmania engages receptors on macrophages and other phagocytes, a series of signaling pathways in the host cell are activated during its internalization, which are critical for establishment and persistence of Leishmania infection. Thus, preventing Leishmania internalization by phagocytes could be a novel therapeutic strategy for leishmaniasis. However, the host cellular machinery that mediates promastigote and amastigote uptake is not well understood. Here, using small molecule inhibitors of Mitogen-activated protein kinases/Extracellular signal regulated kinases (MAPK/ERK), we demonstrate that ERK1/2 mediates Leishmania amazonensis uptake and (to a lesser extent) phagocytosis of beads by macrophages. We find that inhibition of MEK1/2 or ERK1/2 leads to inefficient amastigote uptake by macrophages. Moreover, using inhibitors and primary macrophages lacking spleen tyrosine kinase (SYK) or Abl family kinases, we show that SYK and Abl family kinases mediate Raf, MEK, and ERK1/2 activity and are necessary for efficient uptake. Finally, we demonstrate that trametinib, a MEK1/2 inhibitor used clinically to treat certain cancers, significantly reduces disease severity and parasite burden in Leishmania-infected mice, even if it is started significantly after lesions develop. Our results show that maximal Leishmania infection requires MAPK/ERK and highlight the potential for MAPK/ERK-mediated signaling pathways to be novel therapeutic targets for leishmaniasis.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Added additional supplemental material.

The life cycle alternates between promastigotes, found in the sandfly, and amastigotes, found in mammals. When an infected sandfly bites a host, promastigotes are engulfed by phagocytes ( ., neutrophils, dendritic cells, and macrophages) to establish infection. When these phagocytes die or break down, amastigotes must be re-internalized to survive within the acidic phagolysosome and establish disease. To define host kinase regulators of promastigote and amastigote uptake and survival within macrophages, we performed an image-based kinase regression screen using a panel of 38 kinase inhibitors with unique yet overlapping kinase targets. We also targeted inert beads to complement receptor 3 (CR3) or Fcγ receptors (FcR) as controls by coating them with complement/C3bi or IgG respectively. Through this approach, we identified several putative host kinases that regulate receptor-mediated phagocytosis and/or the uptake of . Findings included kinases previously implicated in uptake (such as Src family kinases (SFK), Abl family kinases (ABL1/c-Abl, ABL2/Arg), and spleen tyrosine kinase (SYK)), but we also uncovered many novel kinases. Our methods also predicted host kinases necessary for promastigotes to convert to amastigotes or for amastigotes to survive within macrophages. Overall, our results suggest that the concerted action of multiple interconnected networks of host kinases are needed over the course of infection, and that the kinases required for the parasite's life cycle may differ substantially depending on which receptors are bound and the life cycle stage that is internalized. In addition, using our screen, we identified kinases that appear to preferentially regulate the uptake of parasites over beads, indicating that the methods required for to be internalized by macrophages may differ significantly from generalized phagocytic mechanisms. Our findings are intended to be used as a hypothesis generation resource for the broader scientific community studying the roles of kinases in host-pathogen interactions.

Leishmania spp. are obligate intracellular parasites that must be internalized by phagocytic cells to evade immune responses and cause disease. Leishmania uptake is thought to be mainly host cell-driven, not parasite-driven. Promastigote (insect-stage) parasites primarily bind complement receptors (e.g., CR3) on phagocytes and are internalized through a process analogous to complement-mediated phagocytosis. Amastigote-stage parasites (proliferative forms in humans and mice) primarily bind Fc receptors and are engulfed through a process similar to immunoglobulin-mediated phagocytosis. Our previous work indicates that host Src and Abl family kinases facilitate Leishmania entry into macrophages and pathogenesis in murine cutaneous leishmaniasis. Here we demonstrate that host spleen tyrosine kinase (SYK) is required for efficient uptake of Leishmania promastigotes and amastigotes. A Src family kinase-Abl family kinase-SYK signaling cascade induces Leishmania amastigote internalization. Finally, lesion size and parasite burden during Leishmania infection is significantly decreased in mice lacking SYK in monocytes or by treatment with the SYK inhibitor entospletinib. In summary, SYK is required for maximal Leishmania uptake by macrophages and disease in mice. Our results suggest potential for treating leishmaniasis using host cell-directed agents.Competing Interest StatementThe authors have declared no competing interest.

Mr. [Mike Johanns] said that what matters most is that the U.S. mad-cow \"firewall\" worked and that the cow was never used as meat or animal feed. \"U.S. beef is safe, plain and simple,\" he told reporters in Washington. \"I enjoyed beef this noon at lunch.\"

Ottawa has allocated almost $2-billion in funding for programs related to mad-cow relief. In Ottawa, U.S. Ambassador Paul Cellucci suggested that Mr. [George W. Bush] will expend some of his political capital to reopen the border. \"It's not only in the interest of the Canadian cattle farmers, but in the interests of the meatpackers of the United States to open that border up,\" he said.