True or false? challenges and recent highlights in the development of aspirin prodrugs

Aspirin is a widely used medicine for a variety of indications. It is unique amongst non-steroidal anti-inflammatory drugs (NSAIDs) in that it causes irreversible acetylation of COX enzymes. Like all NSAIDs however, aspirin causes severe gastrointestinal side-effects, in particular with chronic administration. Prodrugs of aspirin have been proposed as a solution to these side-effects. However, identifying true prodrugs of aspirin, rather than salicylic acid, has proven challenging. This review details the challenges and highlights recent progress in the development of such prodrugs

Fossilized skin reveals coevolution with feathers and metabolism in feathered dinosaurs and early birds

Feathers are remarkable evolutionary innovations that are associated with complex adaptations of the skin in modern birds. Fossilised feathers in non-avian dinosaurs and basal birds provide insights into feather evolution, but how associated integumentary adaptations evolved is unclear. Here we report the discovery of fossil skin, preserved with remarkable nanoscale fidelity, in three non-avian maniraptoran dinosaurs and a basal bird from the Cretaceous Jehol biota (China). The skin comprises patches of desquamating epidermal corneocytes that preserve a cytoskeletal array of helically coiled α-keratin tonofibrils. This structure confirms that basal birds and non-avian dinosaurs shed small epidermal flakes as in modern mammals and birds, but structural differences imply that these Cretaceous taxa had lower body heat production than modern birds. Feathered epidermis acquired many, but not all, anatomically modern attributes close to the base of the Maniraptora by the Middle Jurassic

Development and Validation of a Clinical Scoring System to Differentiate Patients with Inflammatory Bowel Disease and Diarrhea-Predominant Irritable Bowel Disease

Background: There is no validated scoring system for differentiating inflammatory bowel disease (IBD) from irritable bowel syndrome (IBS). Studies variably report clinical measures such as radiology, endoscopy, inflammatory markers, and symptoms to separate IBS from IBD. Our study seeks to create a system to IBD patients from IBS. The “REBISS” score incorporates various clinical criteria used commonly for diagnosis. We also studied a second system called “REBISS-PCP” focusing on a subset of criteria that are available to PCPs when faced with this challenge. Methods: This study was approved by the UMass IRB. Two cohorts were identified: 24 IBD patients (Group1) and 24 IBS patients (Group2). Subjects in Group1 were patients with Crohn’s or ulcerative colitis. Subjects in Group2 were identified as having IBS based on ROME III criteria. Retrospective analysis was performed and a score was calculated. One point is assigned for having: radiological findings consistent with IBD, endoscopic findings of inflammation or ulceration, biopsy findings consistent with IBD, elevated inflammatory markers, weight loss, hematochezia, extra-intestinal signs/symptoms, palpable mass on exam, and perianal disease. The maximum score is 10 points. For the REBISS-PCP score, the same clinical criteria were studied with the exclusion of endoscopic and biopsy findings. Maximum score for that system is 8 points. A likelihood ratio chi-square test was performed for both cohorts and scoring systems. Results: The REBISS scoring system showed a significant differentiation of the two cohorts in regards to scoring distribution (chi-square value = 59.8; p\u3c0.0001). The REBISS-PCP scoring system also found a significant differentiation of the two cohorts (chi-square value = 35.7;p\u3c 0.0001). Discussion: The REBISS scoring system could be used to standardize IBD and IBSd populations in an academic research setting, while both the REBISS and REBISS-PCP scoring system could be used as a screening tool in clinical practice

Angioscopic versus angiographic detection of initial detection of intimal dissection and intracoronary thrombus

AbstractObjectives. This study was undertaken to compare coronary angioscopy with angiography for the detection of intimal dissection and intracoronary thrombus.Background. It has been demonstrated previously that coronary angioscopy provides more intravascular detail than cineangiography. Both imaging methods have to be compared directly to assess the additional diagnostic value of angioscopy.Methods. The angiograms and videotapes of 52 patients who had undergone angioscopy were reviewed independently by two observers unaware of other findings. Classic angiographic definitions were used for dissection and thrombus. Angioscopic dissection was defined as visible cracks or fissures on the lumen surface or mobile protruding structures that are contiguous with the vessel wall. Angioscopic thrombus was defined as a red, white or mixed red and white intraluminal mass.Results. Angiography and angioscopy were in agreement in 40.4% of cases in the absence of thrombus and in 11.5% in the presence of thrombus. No fewer than 25 (48.1%) angioscopically observed thrombi remained undetected at angiography. With angioscopy as the standard, although the specificity of angiography for thrombus was 100%, sensitivity was very low at 19%. Angioscopic dissection was present in 40 patients (76.9%) versus angiographic dissection in 15 patients (28.8%). With regard to dissection, there was no correlation between the two imaging methods (rΦ= 0.15, p = 0.29).Conclusions. Coronary angiography underestimates the presence of intracoronary thrombus. Angioscopy and angiography are complementary techniques for detecting and grading intima1dissections

Standardizing kilonovae and their use as standard candles to measure the Hubble constant

The detection of GW170817 is revolutionizing many areas of astrophysics with the joint observation of gravitational waves and electromagnetic emissions. These multimessenger events provide a new approach to determine the Hubble constant, thus, they are a promising candidate for mitigating the tension between measurements of type-Ia supernovae via the local distance ladder and the cosmic microwave background. In addition to the "standard siren"provided by the gravitational-wave measurement, the kilonova itself has characteristics that allow one to improve existing measurements or to perform yet another, independent measurement of the Hubble constant without gravitational-wave information. Here, we employ standardization techniques borrowed from the type-Ia community and apply them to kilonovae, not using any information from the gravitational-wave signal. We use two versions of this technique, one derived from direct observables measured from the light curve, and the other based on inferred ejecta parameters, e.g., mass, velocity, and composition, for two different models. These lead to Hubble constant measurements of H0=109-35+49 km s-1 Mpc-1 for the measured analysis, and H0=85-17+22 km s-1 Mpc-1 and H0=79-15+23 km s-1 Mpc-1 for the inferred analyses. This measurement has error bars within ∼2 to the gravitational-wave measurements (H0=74-8+16 km s-1 Mpc-1), showing its promise as an independent constraint on H0

Measuring the Hubble constant with a sample of kilonovae

Kilonovae produced by the coalescence of compact binaries with at least one neutron star are promising standard sirens for an independent measurement of the Hubble constant (H0). Through their detection via follow-up of gravitational-wave (GW), short gamma-ray bursts (sGRBs) or optical surveys, a large sample of kilonovae (even without GW data) can be used for H0 contraints. Here, we show measurement of H0 using light curves associated with four sGRBs, assuming these are attributable to kilonovae, combined with GW170817. Including a systematic uncertainty on the models that is as large as the statistical ones, we find H0 ¼ 73:8þ6:3 5:8 km s1 Mpc1 and H0 ¼ 71:2þ3:2 3:1 km s1 Mpc1 for two different kilonova models that are consistent with the local and inverse-distance ladder measurements. For a given model, this measurement is about a factor of 2-3 more precise than the standard-siren measurement for GW170817 using only GWs

Constraints on Type Ia Supernova Progenitor Companions from Early Ultraviolet Observations with Swift

We compare early ultraviolet (UV) observations of Type Ia Supernovae (SNe Ia) with theoretical predictions for the brightness of the shock associated with the collision between SN ejecta and a companion star. Our simple method is independent of the intrinsic flux from the SN and treats the flux observed with the Swift/Ultra-Violet Optical Telescope (UVOT) as conservative upper limits on the shock brightness. Comparing this limit with the predicted flux for various shock models, we constrain the geometry of the SN progenitor-companion system. We find the model of a 1 M_sun red supergiant companion in Roche lobe overflow to be excluded at a 95% confidence level for most individual SNe for all but the most unfavorable viewing angles. For the sample of 12 SNe taken together, the upper limits on the viewing angle are inconsistent with the expected distribution of viewing angles for RG stars as the majority of companions with high confidence. The separation distance constraints do allow MS companions. A better understanding of the UV flux arising from the SN itself as well as continued UV observations of young SNe Ia will further constrain the possible progenitors of SNe Ia.Comment: accepted versio

The Multi-Epoch Nearby Cluster Survey: type Ia supernova rate measurement in z~0.1 clusters and the late-time delay time distribution

We describe the Multi-Epoch Nearby Cluster Survey (MENeaCS), designed to measure the cluster Type Ia supernova (SN Ia) rate in a sample of 57 X-ray selected galaxy clusters, with redshifts of 0.05 < z < 0.15. Utilizing our real time analysis pipeline, we spectroscopically confirmed twenty-three cluster SN Ia, four of which were intracluster events. Using our deep CFHT/Megacam imaging, we measured total stellar luminosities in each of our galaxy clusters, and we performed detailed supernova detection efficiency simulations. Bringing these ingredients together, we measure an overall cluster SN Ia rate within R_{200} (1 Mpc) of 0.042^{+0.012}_{-0.010}^{+0.010}_{-0.008} SNuM (0.049^{+0.016}_{-0.014}^{+0.005}_{-0.004} SNuM) and a SN Ia rate within red sequence galaxies of 0.041^{+0.015}_{-0.015}^{+0.005}_{-0.010} SNuM (0.041^{+0.019}_{-0.015}^{+0.005}_{-0.004} SNuM). The red sequence SN Ia rate is consistent with published rates in early type/elliptical galaxies in the `field'. Using our red sequence SN Ia rate, and other cluster SNe measurements in early type galaxies up to $z\sim1$, we derive the late time (>2 Gyr) delay time distribution (DTD) of SN Ia assuming a cluster early type galaxy star formation epoch of z_f=3. Assuming a power law form for the DTD, \Psi(t)\propto t^s, we find s=-1.62\pm0.54. This result is consistent with predictions for the double degenerate SN Ia progenitor scenario (s\sim-1), and is also in line with recent calculations for the double detonation explosion mechanism (s\sim-2). The most recent calculations of the single degenerate scenario delay time distribution predicts an order of magnitude drop off in SN Ia rate \sim 6-7 Gyr after stellar formation, and the observed cluster rates cannot rule this out.Comment: 35 pages, 14 figures, ApJ accepte

Freshwater Wild Swimming, Health and Well-Being: Understanding the Importance of Place and Risk

Spending time in or around bodies of water or ‘blue spaces’ can benefit human health and well-being. A growing body of evidence suggests immersion in blue space, e.g., participating in ‘wild’ swimming, can be particularly beneficial for both physical and mental health. To date, wild swimming and health research has primarily focused on the experience of individuals who swim in the sea. Empirical studies of the health-promoting potential of swimming in freshwater environments, such as lochs and lakes, are lacking, despite the popularity of this practice in many countries and the vastly different physical and hydrological properties of freshwater and coastal environments. The aim of this study was to explore the relationship between loch (lake) swimming and health and well-being for adults living in Scotland and determine the importance of perceptions of place and risk in this relationship. Semi-structured interviews were conducted with twelve wild swimmers who regularly swim in lochs in Scotland. Interview data were analysed thematically using Nvivo. The findings suggest loch swimming has a variety of health and well-being benefits that can be categorised over three domains of health: physical, mental and social. Of these domains, mental health benefits e.g., mindfulness promotion, resilience building and increasing one’s ability to listen to their body, were particularly prominent. Our findings also highlight important physical and hydrological characteristics of loch environments, e.g., calm water conditions (relative to the sea), which contribute to positive wild swimming experiences. Finally, the perceived risks of loch swimming and mitigation strategies for these risks are established. Collectively, our findings further support the notion that wild swimming is a unique health-promoting practice. Our findings also highlight differences (in terms of experience and perceived risk) between swimming in freshwater and coastal environments, which can inform public health and water management policy