Phosphodiesterase Type 5 Inhibitors and Risk of Malignant Melanoma: Matched Cohort Study Using Primary Care Data from the UK Clinical Practice Research Datalink.

BACKGROUND: Laboratory evidence suggests that reduced phosphodiesterase type 5 (PDE5) expression increases the invasiveness of melanoma cells; hence, pharmacological inhibition of PDE5 could affect melanoma risk. Two major epidemiological studies have investigated this and come to differing conclusions. We therefore aimed to investigate whether PDE5 inhibitor use is associated with an increased risk of malignant melanoma, and whether any increase in risk is likely to represent a causal relationship. METHODS AND FINDINGS: We conducted a matched cohort study using primary care data from the UK Clinical Practice Research Datalink. All men initiating a PDE5 inhibitor and with no prior cancer diagnosis were identified and matched on age, diabetes status, and general practice to up to four unexposed controls. Ever use of a PDE5 inhibitor and time-updated cumulative number of PDE5 inhibitor prescriptions were investigated as exposures, and the primary outcome was malignant melanoma. Basal cell carcinoma, solar keratosis, and colorectal cancer were investigated as negative control outcomes to exclude bias. Hazard ratios (HRs) were estimated from Cox models stratified by matched set and adjusted for potential confounders. 145,104 men with ≥1 PDE5 inhibitor prescription, and 560,933 unexposed matched controls were included. In total, 1,315 incident malignant melanoma diagnoses were observed during 3.44 million person-years of follow-up (mean 4.9 y per person). After adjusting for potential confounders, there was weak evidence of a small positive association between PDE5 inhibitor use and melanoma risk (HR = 1.14, 95% CI 1.01-1.29, p = 0.04). A similar increase in risk was seen for the two negative control outcomes related to sun exposure (HR = 1.15, 95% CI 1.11-1.19, p < 0.001, for basal cell carcinoma; HR = 1.21, 95% CI 1.17-1.25, p < 0.001, for solar keratosis), but there was no increased risk for colorectal cancer (HR = 0.91, 95% CI 0.85-0.98, p = 0.01). There was no evidence that risk increased with number of prescriptions received (p-trend = 0.83). In a post hoc analysis, there was strong evidence that solar keratosis was associated with future PDE5 inhibitor use (odds ratio = 1.28, 95% CI 1.23-1.34, p < 0.001), suggesting that men with higher sun exposure were more likely to become PDE5 inhibitor users. However, a limitation of our study was that we did not have individual-level data on sun exposure, so we could not directly control for this in the primary analysis. CONCLUSIONS: Our results were not consistent with PDE5 inhibitors being causally associated with melanoma risk, and strongly suggest that observed risk increases are driven by greater sun exposure among patients exposed to a PDE5 inhibitor

A search for transits of GJ 581\lowercase{e} and characterization of the host star variability using MOST space telescope photometry

The GJ 581 system has been amply studied since its discovery in 2005: the number of known planets in the system has increased and their orbital parameters are among the most precisely determined for radial velocity detected exoplanets. We have acquired MOST space-based photometry during 2007 and 2009, with the aims of measuring the stellar variability and searching for transits of GJ 581e, respectively. We quantify our sensitivity to shallow transit signals using Monte Carlo simulations, and perform a transit search within the 3$\sigma$ transit windows corresponding to both the circular and Keplerian orbit ephemerides. Our analysis rules out transits for a planet with an orbital period of 3.15 days (GJ 581 e) having a radius larger than 1.62 $R_{\oplus}$ (or a density lower than 2.39 g cm$^{-3}$ for an orbital inclination of 90$^{\circ}$) to 2$\sigma$ confidence. Thus, if the planet transits, we can exclude hydrogen, helium and water theoretical model compositions. The MOST photometry also allows us to rule out transits of GJ 581b within the Keplerian orbit-derived transit window for impact parameter values smaller than $\sim$0.4 and confirm previous results which exclude transits for this planet within the circular orbit-derived transit window, for all plausible interior compositions. We find that the stellar brightness of GJ 581 is stable to within 1%, a characteristic which is favourable to the development of life in the habitable zone of the system. In the 2009 photometry, we detect a stellar signal with a period of 5.586 $\pm$ 0.051 days, which is close to the orbital period of GJ 581b ($P=$5.37 days). However, further monitoring of the system is necessary to verify the nature of this variation.Comment: 11 pages, 2 tables, 10 figures; accepted for publication in Ap

A stable quasi-periodic 4.18 d oscillation and mysterious occultations in the 2011 MOST light curve of TWHya

We present an analysis of the 2011 photometric observations of TW Hya by the MOST satellite; this is the fourth continuous series of this type. The large-scale light variations are dominated by a strong, quasi-periodic 4.18 d oscillation with superimposed, apparently chaotic flaring activity; the former is most likely produced by stellar rotation with one large hot spot created by a stable accretion funnel in the stable regime of accretion while the latter may be produced by small hot spots, created at moderate latitudes by unstable accretion tongues. A new, previously unnoticed feature is a series of semi-periodic, well defined brightness dips of unknown nature of which 19 were observed during 43 days of our nearly-continuous observations. Re-analysis of the 2009 MOST light curve revealed the presence of 3 similar dips. On the basis of recent theoretical results, we tentatively conclude that the dips may represent occultations of the small hot spots created by unstable accretion tongues by hypothetical optically thick clumps.Comment: Printed in MNRA

Photometric variability in FU Ori and Z CMa as observed by MOST

Photometric observations obtained by the MOST satellite were used to characterize optical small scale variability of the young stars FU Ori and Z CMa. Wavelet analysis for FU Ori reveals the possible existence of several 2-9 d quasi-periodic features occurring nearly simultaneously; they may be interpreted as plasma parcels or other localized disc heterogeneities revolving at different Keplerian radii in the accretion disc. Their periods may shorten slowly which may be due to spiralling in of individual parcels toward the inner disc radius, estimated at 4.8+/-0.2 R_sun. Analysis of additional multicolour data confirms the previously obtained relation between variations in the B-V colour index and the V magnitude. In contrast to the FU Ori results, the oscillation spectrum of Z CMa does not reveal any periodicities with the wavelet spectrum possibly dominated by outburst of the Herbig Be component.Comment: Accepted by MNRA

An Upper Limit on the Albedo of HD 209458b: Direct Imaging Photometry with the MOST Satellite

We present space-based photometry of the transiting exoplanetary system HD 209458 obtained with the MOST (Microvariablity and Oscillations of STars) satellite, spanning 14 days and covering 4 transits and 4 secondary eclipses. The HD 209458 photometry was obtained in MOST's lower-precision Direct Imaging mode, which is used for targets in the brightness range $6.5 < V < 13$. We describe the photometric reduction techniques for this mode of observing, in particular the corrections for stray Earthshine. We do not detect the secondary eclipse in the MOST data, to a limit in depth of 0.053 mmag (1 \sigma). We set a 1 \sigma upper limit on the planet-star flux ratio of 4.88 x 10^-5 corresponding to a geometric albedo upper limit in the MOST bandpass (400 to 700 nm) of 0.25. The corresponding numbers at the 3 \sigma level are 1.34 x 10^-4 and 0.68 respectively. HD 209458b is half as bright as Jupiter in the MOST bandpass. This low geometric albedo value is an important constraint for theoretical models of the HD209458b atmosphere, in particular ruling out the presence of reflective clouds. A second MOST campaign on HD 209458 is expected to be sensitive to an exoplanet albedo as low as 0.13 (1 sigma), if the star does not become more intrinsically variable in the meantime.Comment: 29 pages, 9 figures. Accepted for publication in the Astrophysical Journal (July 2006, v645n1

Stable and unstable accretion in the classical T Tauri stars IM Lup and RU Lup as observed by MOST

Results of the time variability monitoring of the two classical T Tauri stars, RU Lup and IM Lup, are presented. Three photometric data sets were utilised: (1) simultaneous (same field) MOST satellite observations over four weeks in each of the years 2012 and 2013, (2) multicolour observations at the SAAO in April - May of 2013, (3) archival V-filter ASAS data for nine seasons, 2001 - 2009. They were augmented by an analysis of high-resolution, public-domain VLT-UT2 UVES spectra from the years 2000 to 2012. From the MOST observations, we infer that irregular light variations of RU Lup are caused by stochastic variability of hot spots induced by unstable accretion. In contrast, the MOST light curves of IM Lup are fairly regular and modulated with a period of about 7.19 - 7.58 d, which is in accord with ASAS observations showing a well defined 7.247+/-0.026 d periodicity. We propose that this is the rotational period of IM Lup and is due to the changing visibility of two antipodal hot spots created near the stellar magnetic poles during the stable process of accretion. Re-analysis of RU Lup high-resolution spectra with the Broadening Function approach reveals signs of a large polar cold spot, which is fairly stable over 13 years. As the star rotates, the spot-induced depression of intensity in the Broadening Function profiles changes cyclically with period 3.71058 d, which was previously found by the spectral cross-correlation method.Comment: 14 pages, 7 figures. Accepted by MNRA

Using MOST to reveal the secrets of the mischievous Wolf-Rayet binary CV Ser

The WR binary CV Serpentis (= WR113, WC8d + O8-9IV) has been a source of mystery since it was shown that its atmospheric eclipses change with time over decades, in addition to its sporadic dust production. The first high-precision time-dependent photometric observations obtained with the MOST space telescope in 2009 show two consecutive eclipses over the 29d orbit, with varying depths. A subsequent MOST run in 2010 showed a seemingly asymmetric eclipse profile. In order to help make sense of these observations, parallel optical spectroscopy was obtained from the Mont Megantic Observatory (2009, 2010) and from the Dominion Astrophysical Observatory (2009). Assuming these depth variations are entirely due to electron scattering in a beta-law wind, an unprecedented 62% increase in mass-loss rate is observed over one orbital period. Alternatively, no change in mass-loss rate would be required if a relatively small fraction of the carbon ions in the wind globally recombined and coaggulated to form carbon dust grains. However, it remains a mystery as to how this could occur. There also seems to be evidence for the presence of corotating interaction regions (CIR) in the WR wind: a CIR-like signature is found in the light curves, implying a potential rotation period for the WR star of 1.6 d. Finally, a new circular orbit is derived, along with constraints for the wind collision.Comment: 11 pages, 11 figures, 5 table

Stratospheric processes: Observations and interpretation

Explaining the observed ozone trends discussed in an earlier update and predicting future trends requires an understanding of the stratospheric processes that affect ozone. Stratospheric processes occur on both large and small spatial scales and over both long and short periods of time. Because these diverse processes interact with each other, only in rare cases can individual processes be studied by direct observation. Generally the cause and effect relationships for ozone changes were established by comparisons between observations and model simulations. Increasingly, these comparisons rely on the developing, observed relationships among trace gases and dynamical quantities to initialize and constrain the simulations. The goal of this discussion of stratospheric processes is to describe the causes for the observed ozone trends as they are currently understood. At present, we understand with considerable confidence the stratospheric processes responsible for the Antarctic ozone hole but are only beginning to understand the causes of the ozone trends at middle latitudes. Even though the causes of the ozone trends at middle latitudes were not clearly determined, it is likely that they, just as those over Antarctica, involved chlorine and bromine chemistry that was enhanced by heterogeneous processes. This discussion generally presents only an update of the observations that have occurred for stratospheric processes since the last assessment (World Meteorological Organization (WMO), 1990), and is not a complete review of all the new information about stratospheric processes. It begins with an update of the previous assessment of polar stratospheres (WMO, 1990), followed by a discussion on the possible causes for the ozone trends at middle latitudes and on the effects of bromine and of volcanoes