A Randomised Phase 2 Trial of Intensive Induction Chemotherapy (CBOP/BEP) and Standard BEP in Poor-prognosis Germ Cell Tumours (MRC TE23, CRUK 05/014, ISRCTN 53643604)

AbstractBackgroundStandard chemotherapy for poor-prognosis metastatic nonseminoma has remained bleomycin, etoposide, and cisplatin (BEP) for many years; more effective regimens are required.ObjectiveTo explore whether response rates with a new intensive chemotherapy regimen, CBOP/BEP (carboplatin, bleomycin, vincristine, cisplatin/BEP), versus those in concurrent patients treated with standard BEP justify a phase 3 trial.Design, setting, and participantsWe conducted a phase 2 open-label randomised trial in patients with germ cell tumours of any extracranial primary site and one or more International Germ Cell Cancer Collaborative Group poor-prognosis features. Patients were randomised between 2005 and 2009 at 16 UK centres.InterventionBEP (bleomycin 30 000 IU) was composed of four cycles over 12 wk. CBOP/BEP was composed of 2×CBOP, 2×BO, and 3×BEP (bleomycin 15 000 IU).Outcome measurements and statistical analysisPrimary end point was favourable response rate (FRR) comprising complete response or partial response and normal markers. Success required the lower two-sided 90% confidence limit to exclude FRRs <60%; 44 patients on CBOP/BEP gives 90% power to achieve this if the true FRR is ≥80%. Equal numbers were randomised to BEP to benchmark contemporary response rates.Results and limitationsA total of 89 patients were randomised (43 CBOP/BEP, 46 BEP); 40 and 41, respectively, completed treatment. CBOP/BEP toxicity, largely haematologic, was high (96% vs 63% on BEP had Common Terminology Criteria for Adverse Events v.3 grade ≥3). FRRs were 74% (90% confidence interval [CI], 61–85) with CBOP/BEP, 61% with BEP (90% CI, 48–73). After a median of 58-mo follow-up, 1-yr progression-free survival (PFS) was 65% and 43%, respectively (hazard ratio: 0.59; 95% CI, 0.33–1.06); 2-yr overall survival (OS) was 67% and 61%. Overall, 3 of 14 CBOP/BEP and 2 of 18 BEP deaths were attributed to toxicity, one after an overdose of bleomycin during CBOP/BEP. The trial was not powered to compare PFS.ConclusionsThe primary outcome was met, the CI for CBOP/BEP excluding FRRs <61%, but CBOP/BEP was more toxic. PFS and OS data are promising but require confirmation in an international phase 3 trial.Patient summaryIn this study we tested a new, more intensive way to deliver a combination of drugs often used to treat men with testicular cancer. We found that response rates were higher but that the CBOP/BEP regimen caused more short-term toxicity. Because most patients are diagnosed when their cancer is less advanced, it took twice as long to complete the trial as expected. Although we plan to carry out a larger trial, we will need international collaboration.Trial registrationISRCTN53643604; http://www.controlled-trials.com/ISRCTN53643604

Sharing the Rewards, Dividing the Costs? The Electoral Consequences of Social Pacts and Legislative Reform in Western Europe

Research suggests that electoral pressures may provide an explanation for why governments offer pacts to unions and employers rather than acting through legislation when faced with the need to pass potentially unpopular reforms to welfare policies, wages, and labour markets. Here, we analyse whether governments’ pursuit of pacts affects their vote share and increases the probability that they gain re-election for 16 West European countries between 1980 and 2012. We find that the presence of social pacts has a significant and positive effect on incumbents’ vote shares at the next election and also results in a higher probability of re-election. While all types of governments benefit electorally from pacts, the electoral penalties from the pursuit of unilateral legislation on policy reforms harm single-party majorities the most, minority governments moderately, and coalition majorities the least

Cofilin interacts with ClC-5 and regulates albumin uptake in proximal tubule cell lines

Receptor-mediated endocytosis is a constitutive high capacity pathway for the reabsorption of proteins from the glomerular filtrate by the renal proximal tubule. ClC-5 is a voltage-gated chloride channel found in the proximal tubule where it has been shown to be essential for protein uptake, based on evidence from patients with Dent's disease and studies in ClC-5 knockout mice. To further delineate the role of ClC-5 in albumin uptake, we performed a yeast two-hybrid screen with the C-terminal tail of ClC-5 to identify any interactions of the channel with proteins involved in endocytosis. We found that the C-terminal tail of ClC-5 bound the actin depolymerizing protein, cofilin, a result that was confirmed by GST-fusion pulldown assays. In cultured proximal tubule cells, cofilin was distributed in nuclear, cytoplasmic, and microsomal fractions and co-localized with ClC-5. Phosphorylation of cofilin by overexpressing LIM kinase 1 resulted in a stabilization of the actin cytoskeleton. Phosphorylation of cofilin in two proximal tubule cell models (porcine renal proximal tubule and opossum kidney) was also accompanied by a pronounced inhibition of albumin uptake. This study identifies a novel interaction between the C-terminal tail of ClC-5 and cofilin, an actin-associated protein that is crucial in the regulation of albumin uptake by the proximal tubule

Orbiting Carbon Observatory-2 (OCO-2) cloud screening algorithms: validation against collocated MODIS and CALIOP data

The objective of the National Aeronautics and Space Administration's (NASA) Orbiting Carbon Observatory-2 (OCO-2) mission is to retrieve the column-averaged carbon dioxide (CO₂) dry air mole fraction (XCO2) from satellite measurements of reflected sunlight in the near-infrared. These estimates can be biased by clouds and aerosols, i.e., contamination, within the instrument's field of view. Screening of the most contaminated soundings minimizes unnecessary calls to the computationally expensive Level 2 (L2) X_(CO₂) retrieval algorithm. Hence, robust cloud screening methods have been an important focus of the OCO-2 algorithm development team. Two distinct, computationally inexpensive cloud screening algorithms have been developed for this application. The A-Band Preprocessor (ABP) retrieves the surface pressure using measurements in the 0.76 µm O₂ A band, neglecting scattering by clouds and aerosols, which introduce photon path-length differences that can cause large deviations between the expected and retrieved surface pressure. The Iterative Maximum A Posteriori (IMAP) Differential Optical Absorption Spectroscopy (DOAS) Preprocessor (IDP) retrieves independent estimates of the CO₂ and H₂O column abundances using observations taken at 1.61 µm (weak CO₂ band) and 2.06 µm (strong CO₂ band), while neglecting atmospheric scattering. The CO₂ and H₂O column abundances retrieved in these two spectral regions differ significantly in the presence of cloud and scattering aerosols. The combination of these two algorithms, which are sensitive to different features in the spectra, provides the basis for cloud screening of the OCO-2 data set. To validate the OCO-2 cloud screening approach, collocated measurements from NASA's Moderate Resolution Imaging Spectrometer (MODIS), aboard the Aqua platform, were compared to results from the two OCO-2 cloud screening algorithms. With tuning of algorithmic threshold parameters that allows for processing of  ≃ 20–25 % of all OCO-2 soundings, agreement between the OCO-2 and MODIS cloud screening methods is found to be  ≃ 85 % over four 16-day orbit repeat cycles in both the winter (December) and spring (April–May) for OCO-2 nadir-land, glint-land and glint-water observations. No major, systematic, spatial or temporal dependencies were found, although slight differences in the seasonal data sets do exist and validation is more problematic with increasing solar zenith angle and when surfaces are covered in snow and ice and have complex topography. To further analyze the performance of the cloud screening algorithms, an initial comparison of OCO-2 observations was made to collocated measurements from the Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP) aboard the Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO). These comparisons highlight the strength of the OCO-2 cloud screening algorithms in identifying high, thin clouds but suggest some difficulty in identifying some clouds near the surface, even when the optical thicknesses are greater than 1

Exploration of the altar painting “Sacra Conversazione” by Bernardino Licinio from the church of St. Francis in Krk

Slika Sacra Conversazione Bernardina Licinija iz crkve Sv. Franje Asiškog u Krku izrađena je tehnikom masne tempere na dasci. Velike dimenzije slike u kombinaciji sa smještajem na visini uz teška oštećenja nosioca i slikanih slojeva, zahtijevala su izvođenje konzervatorsko-restauratorskih istraživanja in situ. Tom je prilikom prvi put u Hrvatskoj izvan radionice, na terenu, primijenjena vizualizacija oltarne pale velikog formata računalnom radiografjom. Omogućila je uvid u stanje nosioca i slikanih slojeva, smanjila rizik demontaže i transporta te usmjerila daljnje konzervatorsko-restauratorske radove.The altar pala Sacra Conversazione, by Bernardino Licinio (Venice, 1485/1489–c. 1550), is located on the main altar of the Church of St. Francis in the town of Krk. It was painted in 1531 in tempera grassa on board. In contrast to the later Venetian Sacra Conversazione by the same artist, painted in 1535, the Krk pala is almost completely unknown in professional literature; it is mentioned only in some older literature, with a short iconographic description. Due to the painting’s large dimensions (280x195 cm) and weight, its location high on the main altar, and the significant damage to the painted layers, its wooden base and the support system, the conservation-restoration explorations were carried out in situ, at the church altar. This significantly reduced the possibility of additional damage being incurred during dismantling and transport. The artefact was filmed in the visible, UV and IR parts of the spectrum, and under slanted light. Samples of pigment and binding material were analysed in a laboratory, and the order of layers was established. A particularly interesting phase of the conservation-restoration exploration was the visualization of the artefact by computer radiography. This method, created and developed for medical purposes, is being applied ever more often in restoration for exploring and documenting artefacts. Prior to this occasion, it had not been used in Croatia for in situ explorations. The visualization of the Krk pala by computer radiography made it possible to assess the condition of the original painted layer, wooden base and support system, which is normally hidden by the large wall at the back of the altar. The computer radiography uncovered grave and extensive damage to the painting base and the painted layers, but which can be remedied and reconstructed. Exploratory attempts to remove the “secondary” coats from the surface of the original painted layer suggested that several interventions had already been made on the artefact, two of them rather substantial, and they included reduction of the altar painting’s format. The explorations carried out thus far have provided the basic information on this artefact, which will be supplemented by further restoration procedures, and archival and art-historical research

The mechanisms and processes of connection: developing a causal chain model capturing impacts of receiving recorded mental health recovery narratives.

BACKGROUND: Mental health recovery narratives are a core component of recovery-oriented interventions such as peer support and anti-stigma campaigns. A substantial number of recorded recovery narratives are now publicly available online in different modalities and in published books. Whilst the benefits of telling one's story have been investigated, much less is known about how recorded narratives of differing modalities impact on recipients. A previous qualitative study identified connection to the narrator and/or to events in the narrative to be a core mechanism of change. The factors that influence how individuals connect with a recorded narrative are unknown. The aim of the current study was to characterise the immediate effects of receiving recovery narratives presented in a range of modalities (text, video and audio), by establishing the mechanisms of connection and the processes by which connection leads to outcomes. METHOD: A study involving 40 mental health service users in England was conducted. Participants were presented with up to 10 randomly-selected recovery narratives and were interviewed on the immediate impact of each narrative. Thematic analysis was used to identify the mechanisms of connection and how connection leads to outcome. RESULTS: Receiving a recovery narrative led participants to reflect upon their own experiences or those of others, which then led to connection through three mechanisms: comparing oneself with the narrative and narrator; learning about other's experiences; and experiencing empathy. These mechanisms led to outcomes through three processes: the identification of change (through attending to narrative structure); the interpretation of change (through attending to narrative content); and the internalisation of interpretations. CONCLUSIONS: This is the first study to identify mechanisms and processes of connection with recorded recovery narratives. The empirically-based causal chain model developed in this study describes the immediate effects on recipients. This model can inform selection of narratives for use in interventions, and be used to support peer support workers in recounting their own recovery narratives in ways which are maximally beneficial to others

Metabolic Factors Limiting Performance in Marathon Runners

Each year in the past three decades has seen hundreds of thousands of runners register to run a major marathon. Of those who attempt to race over the marathon distance of 26 miles and 385 yards (42.195 kilometers), more than two-fifths experience severe and performance-limiting depletion of physiologic carbohydrate reserves (a phenomenon known as ‘hitting the wall’), and thousands drop out before reaching the finish lines (approximately 1–2% of those who start). Analyses of endurance physiology have often either used coarse approximations to suggest that human glycogen reserves are insufficient to fuel a marathon (making ‘hitting the wall’ seem inevitable), or implied that maximal glycogen loading is required in order to complete a marathon without ‘hitting the wall.’ The present computational study demonstrates that the energetic constraints on endurance runners are more subtle, and depend on several physiologic variables including the muscle mass distribution, liver and muscle glycogen densities, and running speed (exercise intensity as a fraction of aerobic capacity) of individual runners, in personalized but nevertheless quantifiable and predictable ways. The analytic approach presented here is used to estimate the distance at which runners will exhaust their glycogen stores as a function of running intensity. In so doing it also provides a basis for guidelines ensuring the safety and optimizing the performance of endurance runners, both by setting personally appropriate paces and by prescribing midrace fueling requirements for avoiding ‘the wall.’ The present analysis also sheds physiologically principled light on important standards in marathon running that until now have remained empirically defined: The qualifying times for the Boston Marathon

In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs

Comment in Lowering the High Cost of Cancer Drugs--III. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--I. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--IV. [Mayo Clin Proc. 2016] In Reply--Lowering the High Cost of Cancer Drugs. [Mayo Clin Proc. 2016] US oncologists call for government regulation to curb drug price rises. [BMJ. 2015

Contrasting Transcriptional Responses of a Virulent and an Attenuated Strain of Mycobacterium tuberculosis Infecting Macrophages

Along with the recent identification of single nucleotide polymorphisms in H37Ra when compared to H37Rv, our demonstration of differential expression of PhoP-regulated and ESX-1 region-related genes during macrophage infection further highlights the significance of these genes in the attenuation of H37Ra