Cost Effectiveness of First-Line Treatment with Doxorubicin/Ifosfamide Compared to Trabectedin Monotherapy in the Management of Advanced Soft Tissue Sarcoma in Italy, Spain, and Sweden

BACKGROUND: Doxorubicin/ifosfamide is a first-line systemic chemotherapy for the majority of advanced soft tissue sarcoma (ASTS) subtypes. Trabectedin is indicated for the treatment of ASTS after failure of anthracyclines and/or ifosfamide; however it is being increasingly used off-label as a first-line treatment. This study estimated the cost effectiveness of these two treatments in the first-line management of ASTS in Italy, Spain, and Sweden. METHODS: A Markov model was constructed to estimate the cost effectiveness of doxorubicin/ifosfamide compared to trabectedin monotherapy, defined as the cost per QALY gained, in each country. RESULTS: First-line treatment with doxorubicin/ifosfamide resulted in lower two-year healthcare costs and more QALYs than first-line treatment with trabectedin monotherapy in all three countries. Probabilistic sensitivity analysis showed that at a cost per QALY threshold of €35,000, >90% of a cohort would be cost effectively treated with doxorubicin/ifosfamide compared to trabectedin monotherapy in all three countries. CONCLUSION: Within the model’s limitations, first-line treatment of patients with ASTS with doxorubicin/ifosfamide instead of trabectedin monotherapy affords a cost-effective use of publicly funded healthcare resources in Italy, Spain, and Sweden and is therefore the preferred treatment in all three countries. These findings support the recommendation that trabectedin should remain a second-line treatment

Increased insolation threshold for runaway greenhouse processes on Earth like planets

Because the solar luminosity increases over geological timescales, Earth climate is expected to warm, increasing water evaporation which, in turn, enhances the atmospheric greenhouse effect. Above a certain critical insolation, this destabilizing greenhouse feedback can "runaway" until all the oceans are evaporated. Through increases in stratospheric humidity, warming may also cause oceans to escape to space before the runaway greenhouse occurs. The critical insolation thresholds for these processes, however, remain uncertain because they have so far been evaluated with unidimensional models that cannot account for the dynamical and cloud feedback effects that are key stabilizing features of Earth's climate. Here we use a 3D global climate model to show that the threshold for the runaway greenhouse is about 375 W/m$^2$, significantly higher than previously thought. Our model is specifically developed to quantify the climate response of Earth-like planets to increased insolation in hot and extremely moist atmospheres. In contrast with previous studies, we find that clouds have a destabilizing feedback on the long term warming. However, subsident, unsaturated regions created by the Hadley circulation have a stabilizing effect that is strong enough to defer the runaway greenhouse limit to higher insolation than inferred from 1D models. Furthermore, because of wavelength-dependent radiative effects, the stratosphere remains cold and dry enough to hamper atmospheric water escape, even at large fluxes. This has strong implications for Venus early water history and extends the size of the habitable zone around other stars.Comment: Published in Nature. Online publication date: December 12, 2013. Accepted version before journal editing and with Supplementary Informatio

The pathogenesis of Charcot neuroarthropathy: current concepts

The pathogenesis of Charcot neuroarthropathy (CN) has been poorly understood by clinicians and scientists alike. Current researchers have made progress toward understanding the cause of CN and possible treatment options. The authors review the current literature on the pathogenesis of this debilitating disorder and attempt to explain the roles of inflammation, bone metabolism, and advanced glycation end products

Demography and disorders of German Shepherd Dogs under primary veterinarycare in the UK

The German Shepherd Dog (GSD) has been widely used for a variety of working roles. However, concerns for the health and welfare of the GSD have been widely aired and there is evidence that breed numbers are now in decline in the UK. Accurate demographic and disorder data could assist with breeding and clinical prioritisation. The VetCompassTM Programme collects clinical data on dogs under primary veterinary care in the UK. This study included all VetCompassTM dogs under veterinary care during 2013. Demographic, mortality and clinical diagnosis data on GSDs were extracted and reported

Border Terriers under primary veterinary care in England: demography and disorders

The Border Terrier is a working terrier type that is generally considered to be a relatively healthy and hardy breed. This study aimed to characterise the demography and common disorders of Border Terriers receiving veterinary care in England using de-identified electronic patient record data within the VetCompass™ Programme

Extreme sensitivity in Snowball Earth formation to mountains on PaleoProterozoic supercontinents

During the PaleoProterozoic 2.45 to 2.2 billion years ago, several glaciations may have produced Snowball Earths. These glacial cycles occurred during large environmental change when atmospheric oxygen was increasing, a supercontinent was assembled from numerous landmasses, and collisions between these landmasses formed mountain ranges. Despite uncertainties in the composition of the atmosphere and reconstruction of the landmasses, paleoclimate model simulations can test the sensitivity of the climate to producing a Snowball Earth. Here we present a series of simulations that vary the atmospheric methane concentration and latitudes of west–east-oriented mountain ranges on an idealised supercontinent. For a given methane concentration, the latitudes of mountains control whether a Snowball Earth forms or not. Significantly, mountains in middle latitudes inhibited Snowball Earth formation, and mountains in low latitudes promoted Snowball Earth formation, with the supercontinent with mountains at ±30° being most conducive to forming a Snowball Earth because of reduced albedo at low latitudes. We propose that the extreme sensitivity of a Snowball Earth to reconstructions of the paleogeography and paleoatmospheric composition may explain the observed glaciations, demonstrating the importance of high-quality reconstructions to improved understanding of this early period in Earth’s history

Increased osteoclastic activity in acute Charcot’s osteoarthopathy: the role of receptor activator of nuclear factor-kappaB ligand

Aims/hypothesis: Our aims were to compare osteoclastic activity between patients with acute Charcot's osteoarthropathy and diabetic and healthy controls, and to determine the effect of the receptor activator of nuclear factor-kappaB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG). Methods: Peripheral blood monocytes isolated from nine diabetic Charcot patients, eight diabetic control and eight healthy control participants were cultured in the presence of macrophage-colony stimulating factor (M-CSF) alone, M-CSF and RANKL, and also M-CSF and RANKL with excess concentrations of OPG. Osteoclast formation was assessed by expression of tartrate-resistant acid phosphatase on glass coverslips and resorption on dentine slices. Results: In cultures with M-CSF, there was a significant increase in osteoclast formation in Charcot patients compared with healthy and diabetic control participants (p=0.008). A significant increase in bone resorption was also seen in the former, compared with healthy and diabetic control participants (p<0.0001). The addition of RANKL to the cultures with M-CSF led to marked increase in osteoclastic resorption in Charcot (from 0.264±0.06% to 41.6±8.1%, p<0.0001) and diabetic control (0.000±0.00% to 14.2±16.5%, p<0.0001) patients, and also in healthy control participants (0.004±0.01% to 10.5±1.9%, p0.0001). Although the addition of OPG to cultures with M-CSF and RANKL led to a marked reduction of resorption in Charcot patients (41.6±8.1% to 5.9±2.4%, p=0.001), this suppression was not as complete as in diabetic control patients (14.2±16.5% to 0.45±0.31%, p=0.001) and in healthy control participants (from 10.5±1/9% to 0.00±0.00%, p<0.0001). Conclusions/interpretation: These results indicate that RANKL-mediated osteoclastic resorption occurs in acute Charcot's osteoarthropathy. However, the incomplete inhibition of RANKL after addition of OPG also suggests the existence of a RANKL-independent pathway

Influence of arthritis and non-arthritis related factors on areal bone mineral density (BMDa) in women with longstanding inflammatory polyarthritis: a primary care based inception cohort

<p>Abstract</p> <p>Background</p> <p>The aim of this analysis was to determine the relative influence of disease and non-disease factors on areal bone mineral density (BMD_a) in a primary care based cohort of women with inflammatory polyarthritis.</p> <p>Methods</p> <p>Women aged 16 years and over with recent onset inflammatory polyarthritis were recruited to the Norfolk Arthritis Register (NOAR) between 1990 and 1993. Subjects were examined at both baseline and follow up for the presence of tender, swollen and deformed joints. At the 10^thanniversary visit, a sub-sample of women were invited to complete a bone health questionnaire and attend for BMD_a(Hologic, QDR 4000). Linear regression was used to examine the association between BMD_awith both (i) arthritis-related factors assessed at baseline and the 10^thanniversary visit and (ii) standard risk factors for osteoporosis. Adjustments were made for age.</p> <p>Results</p> <p>108 women, mean age 58.0 years were studied. Older age, decreasing weight and BMI at follow up were all associated with lower BMD_aat both the spine and femoral neck. None of the lifestyle factors were linked. Indices of joint damage including 10^thanniversary deformed joint count and erosive joint count were the arthritis-related variables linked with a reduction in BMD_aat the femoral neck. By contrast, disease activity as determined by the number of tender and or swollen joints assessed both at baseline and follow up was not linked with BMD_aat either site.</p> <p>Conclusion</p> <p>Cumulative disease damage was the strongest predictor of reduced femoral bone density. Other disease and lifestyle factors have only a modest influence.</p