White-light stellar flares are proxies for some of the most energetic types of flares, but their triggering mechanism is still poorly understood. As they are associated with strong X and ultraviolet ...emission, their study is particularly relevant to estimate the amount of high-energy irradiation onto the atmospheres of exoplanets, especially those in their stars' habitable zone. We used the high-cadence, high-photometric capabilities of the CHEOPS and TESS space telescopes to study the detailed morphology of white-light flares occurring in a sample of 130 late-K and M stars, and compared our findings with results obtained at a lower cadence. We employed dedicated software for the reduction of 3 s cadence CHEOPS data, and adopted the 20 s cadence TESS data reduced by their official processing pipeline. We developed an algorithm to separate multi-peak flare profiles into their components, in order to contrast them to those of single-peak, classical flares. We also exploited this tool to estimate amplitudes and periodicities in a small sample of quasi-periodic pulsation (QPP) candidates. Complex flares represent a significant percentage ($ 30<!PCT!>$) of the detected outburst events. Our findings suggest that high-impulse flares are more frequent than suspected from lower-cadence data, so that the most impactful flux levels that hit close-in exoplanets might be more time-limited than expected. We found significant differences in the duration distributions of single and complex flare components, but not in their peak luminosity. A statistical analysis of the flare parameter distributions provides marginal support for their description with a log-normal instead of a power-law function, leaving the door open to several flare formation scenarios. We tentatively confirmed previous results about QPPs in high-cadence photometry, report the possible detection of a pre-flare dip, and did not find hints of photometric variability due to an undetected flare background. The high-cadence study of stellar hosts might be crucial to evaluate the impact of their flares on close-in exoplanets, as their impulsive phase emission might otherwise be incorrectly estimated. Future telescopes such as PLATO and Ariel, thanks to their high-cadence capability, will help in this respect. As the details of flare profiles and of the shape of their parameter distributions are made more accessible by continuing to increase the instrument precision and time resolution, the models used to interpret them and their role in star-planet interactions might need to be updated constantly.
Aims/hypothesis Observational and mechanistic studies have suggested a possible relationship between treatment with metformin and decreased incidence of cancer in participants with type 2 diabetes. ...We extracted data for malignancies from the ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) randomised controlled clinical trials, in which the efficacy and/or safety of metformin was assessed in comparison with sulfonylureas and rosiglitazone. Methods Neoplasm occurrences were collected as adverse events in these studies. We reviewed and re-analysed the individual participant data in both studies for serious adverse events, malignancies reported as adverse events and related neoplasms of special interest. Results In ADOPT, 50 participants (3.4%) on metformin and 55 (3.8%) on each of rosiglitazone and glibenclamide (known as glyburide in the USA and Canada) developed serious adverse event malignancies (excluding non-melanoma skin cancers). This corresponds to 1.03, 1.12 and 1.31 per 100 person-years, giving hazard ratios for metformin of 0.92 (95% CI 0.63-1.35) vs rosiglitazone and 0.78 (0.53-1.14) vs glibenclamide. In RECORD, on a background of sulfonylurea, 69 (6.1%) participants developed malignant neoplasms in the metformin group, compared with 56 (5.1%) in the rosiglitazone group (HR 1.22 0.86-1.74). On a background of metformin, 74 (6.7%) participants in the sulfonylurea group developed malignant neoplasms, compared with 57 (5.1%) in the rosiglitazone group (HR 1.33 0.94-1.88). Conclusions/interpretation The malignancy rates in these two randomised controlled clinical trials do not support a view that metformin offers any particular protection against malignancy compared with rosiglitazone. However, they do not refute the possibility of a difference compared with sulfonylureas.
Abstract Aim Final 10-year analysis of the prospective randomised Chemo-N0 trial is presented. Based on the Chemo-N0 interim results and an European Organisation for Research and Treatment of Cancer ...(EORTC) pooled analysis ( n = 8377), American Society of Clinical Oncology (ASCO) and Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) guidelines recommend invasion and metastasis markers urokinase-type plasminogen activator (uPA)/plasminogen activator inhibitor-1 (PAI-1) for risk assessment and treatment decision in node-negative (N0) breast cancer (BC). Methods The final Chemo-N0 trial analysis (recruitment 1993–1998; n = 647; 12 centres) comprises 113 (5-167) months of median follow-up. Patients with low-uPA and PAI-1 tumour tissue levels ( n = 283) were observed. External quality assurance guaranteed uPA/PAI-1 enzyme-linked immunosorbent assay (ELISA) standardisation. Of 364 high uPA and/or PAI-1 patients, 242 agreed to randomisation for CMF chemotherapy ( n = 117) versus observation ( n = 125). Results Actuarial 10-year recurrence rate (without any adjuvant systemic therapy) for high-uPA/PAI-1 observation group patients (randomised and non-randomised) was 23.0%, in contrast to only 12.9% for low-uPA/PAI-1 patients ( plog-rank = 0.011). High-risk patients randomised to cyclophosphamide-methotrexate-5-fluorouracil (CMF) therapy had a 26.0% lower estimated probability of disease recurrence than those randomised for observation (intention-to-treat (ITT)-analysis: hazard ratio (HR) 0.74 (0.44–1.27); plog-rank = 0.28). Per-protocol analysis demonstrated significant treatment benefit: HR 0.48 (0.26–0.88), p = 0.019, disease-free survival (DFS) Cox regression, adjusted for tumour stage and grade. Conclusions Chemo-N0 is the first prospective biomarker-based therapy trial in early BC defining patients reaching good long-term DFS without adjuvant systemic therapy. Using a standardised uPA/PAI-1 ELISA, almost half of N0-patients could be spared chemotherapy, while high-risk patients benefit from adjuvant chemotherapy. These 10-year results validate the long-term prognostic impact of uPA/PAI-1 and the benefit from adjuvant chemotherapy in the high-uPA/PAI-1 group at highest level of evidence. They thus support the guideline-based routine use of uPA/PAI-1 for risk-adapted individualised therapy decisions in N0 breast cancer.
Improved understanding of the lung microbiome in HIV-infected individuals could lead to better strategies for diagnosis, therapy, and prophylaxis of HIV-associated pneumonias. Differences in the oral ...and lung microbiomes in HIV-infected and HIV-uninfected individuals are not well defined. Whether highly active antiretroviral therapy influences these microbiomes is unclear.
We determined whether oral and lung microbiomes differed in clinically healthy groups of HIV-infected and HIV-uninfected subjects.
Participating sites in the Lung HIV Microbiome Project contributed bacterial 16S rRNA sequencing data from oral washes and bronchoalveolar lavages (BALs) obtained from HIV-uninfected individuals (n = 86), HIV-infected individuals who were treatment naive (n = 18), and HIV-infected individuals receiving antiretroviral therapy (n = 38).
Microbial populations differed in the oral washes among the subject groups (Streptococcus, Actinomyces, Rothia, and Atopobium), but there were no individual taxa that differed among the BALs. Comparison of oral washes and BALs demonstrated similar patterns from HIV-uninfected individuals and HIV-infected individuals receiving antiretroviral therapy, with multiple taxa differing in abundance. The pattern observed from HIV-infected individuals who were treatment naive differed from the other two groups, with differences limited to Veillonella, Rothia, and Granulicatella. CD4 cell counts did not influence the oral or BAL microbiome in these relatively healthy, HIV-infected subjects.
The overall similarity of the microbiomes in participants with and without HIV infection was unexpected, because HIV-infected individuals with relatively preserved CD4 cell counts are at higher risk for lower respiratory tract infections, indicating impaired local immune function.
The most prevalent pathogen in bone infections is Staphylococcus aureus; its incidence and severity are partially determined by host factors. Prior studies showed that anti-glucosaminidase (Gmd) ...antibodies are protective in animals, and 93.3 % of patients with culture-confirmed S. aureus osteomyelitis do not have anti-Gmd levels > 10 ng/mL in serum. Infection in patients with high anti-Gmd remains unexplained. Are anti-Gmd antibodies in osteomyelitis patients of the non-opsonising, non-complement-fixing IgG4 isotype? The relative amounts of IgG4 and total IgG against Gmd and 7 other S. aureus antigens: iron-surface determinants (Isd) IsdA, IsdB, and IsdH, amidase (Amd), α-haemolysin (Hla), chemotaxis inhibitory protein from S. aureus (CHIPS), and staphylococcal-complement inhibitor (SCIN) were determined in sera from healthy controls (Ctrl, n = 92), osteomyelitis patients whose surgical treatment resulted in infection control (IC, n = 95) or an adverse outcome (AD, n = 40), and post-mortem (PM, n = 7) blood samples from S. aureus septic-death patients. Anti-Gmd IgG4 levels were generally lower in infected patients compared to controls; however, levels among the infected were higher in AD than IC patients. Anti-IsdA, IsdB and IsdH IgG4 levels were increased in infected patients versus controls, and Jonckheere-Terpstra tests of levels revealed an increasing order of infection (Ctrl < IC < AD < PM) for anti-Isd IgG4 antibodies and a decreasing order of infection (Ctrl > IC > AD > PM) for anti-autolysin (Atl) IgG4 antibodies. Collectively, this does not support an immunosuppressive role of IgG4 in S. aureus osteomyelitis but is consistent with a paradigm of high anti-Isd and low anti-Atl responses in these patients.
Both the amount of dialysis and the size of the molecules removed may influence morbidity and mortality among patients receiving long-term hemodialysis. The multicenter Hemodialysis Study randomly ...assigned 1846 patients, according to a two-by-two factorial design, either to the standard dialysis dose currently recommended in the United States or to a high dialysis dose, with either a high-flux or a low-flux dialyzer. Neither mortality from any cause nor morbidity differed between the groups during a mean follow-up of 2.84 years.
There was no major benefit from increasing the dialysis dose or from switching to high-flux membranes.
Two treatment-related factors implicated in the substantial mortality and morbidity among patients undergoing maintenance hemodialysis
1
are the dose of dialysis delivered and the size of molecules removed. An index of the dialysis dose is the fractional clearance of urea (molecular mass, 60 D) which is commonly expressed as the intradialytic urea-reduction ratio
2
or as Kt/V, where K represents the rate of urea clearance by the dialyzer in milliliters per minute, t the duration in minutes of the treatment session, and V the volume of distribution of urea in the patient in milliliters.
3
Current guidelines in the United States target a . . .
Glioblastoma (GBM), the most malignant tumor of the central nervous system, is marked by its dynamic response to microenvironmental niches. In particular, this cellular plasticity contributes to the ...development of an immediate resistance during tumor treatment. Novel insights into the developmental trajectory exhibited by GBM show a strong capability to respond to its microenvironment by clonal selection of specific phenotypes. Using the same mechanisms, malignant GBM do develop intrinsic mechanisms to resist chemotherapeutic treatments. This resistance was reported to be sustained by the paracrine and autocrine glutamate signaling via ionotropic and metabotropic receptors. However, the extent to which glutamatergic signaling modulates the chemoresistance and transcriptional profile of the GBM remains unexplored. In this study we aimed to map the manifold effects of glutamate signaling in GBM as the basis to further discover the regulatory role and interactions of specific receptors, within the GBM microenvironment. Our work provides insights into glutamate release dynamics, representing its importance for GBM growth, viability, and migration. Based on newly published multi-omic datasets, we explored the and characterized the functions of different ionotropic and metabotropic glutamate receptors, of which the metabotropic receptor 3 (GRM3) is highlighted through its modulatory role in maintaining the ability of GBM cells to evade standard alkylating chemotherapeutics. We addressed the clinical relevance of GRM3 receptor expression in GBM and provide a proof of concept where we manipulate intrinsic mechanisms of chemoresistance, driving GBM towards chemo-sensitization through GRM3 receptor inhibition. Finally, we validated our findings in our novel human organotypic section-based tumor model, where GBM growth and proliferation was significantly reduced when GRM3 inhibition was combined with temozolomide application. Our findings present a new picture of how glutamate signaling via mGluR3 interacts with the phenotypical GBM transcriptional programs in light of recently published GBM cell-state discoveries.
Big data and extreme-scale computing Asch, M; Moore, T; Badia, R ...
The international journal of high performance computing applications,
07/2018, Letnik:
32, Številka:
4
Journal Article
Recenzirano
Over the past four years, the Big Data and Exascale Computing (BDEC) project organized a series of five international workshops that aimed to explore the ways in which the new forms of data-centric ...discovery introduced by the ongoing revolution in high-end data analysis (HDA) might be integrated with the established, simulation-centric paradigm of the high-performance computing (HPC) community. Based on those meetings, we argue that the rapid proliferation of digital data generators, the unprecedented growth in the volume and diversity of the data they generate, and the intense evolution of the methods for analyzing and using that data are radically reshaping the landscape of scientific computing. The most critical problems involve the logistics of wide-area, multistage workflows that will move back and forth across the computing continuum, between the multitude of distributed sensors, instruments and other devices at the networks edge, and the centralized resources of commercial clouds and HPC centers. We suggest that the prospects for the future integration of technological infrastructures and research ecosystems need to be considered at three different levels. First, we discuss the convergence of research applications and workflows that establish a research paradigm that combines both HPC and HDA, where ongoing progress is already motivating efforts at the other two levels. Second, we offer an account of some of the problems involved with creating a converged infrastructure for peripheral environments, that is, a shared infrastructure that can be deployed throughout the network in a scalable manner to meet the highly diverse requirements for processing, communication, and buffering/storage of massive data workflows of many different scientific domains. Third, we focus on some opportunities for software ecosystem convergence in big, logically centralized facilities that execute large-scale simulations and models and/or perform large-scale data analytics. We close by offering some conclusions and recommendations for future investment and policy review.
ABSTRACT
HIP 9618 (HD 12572, TOI-1471, TIC 306263608) is a bright (G = 9.0 mag) solar analogue. TESS photometry revealed the star to have two candidate planets with radii of 3.9 ± 0.044 R⊕ (HIP 9618 ...b) and 3.343 ± 0.039 R⊕ (HIP 9618 c). While the 20.77291 d period of HIP 9618 b was measured unambiguously, HIP 9618 c showed only two transits separated by a 680-d gap in the time series, leaving many possibilities for the period. To solve this issue, CHEOPS performed targeted photometry of period aliases to attempt to recover the true period of planet c, and successfully determined the true period to be 52.56349 d. High-resolution spectroscopy with HARPS-N, SOPHIE, and CAFE revealed a mass of 10.0 ± 3.1M⊕ for HIP 9618 b, which, according to our interior structure models, corresponds to a $6.8\pm 1.4~{{\ \rm per\ cent}}$ gas fraction. HIP 9618 c appears to have a lower mass than HIP 9618 b, with a 3-sigma upper limit of <18M⊕. Follow-up and archival RV measurements also reveal a clear long-term trend which, when combined with imaging and astrometric information, reveal a low-mass companion ($0.08^{+0.12}_{-0.05} M_\odot$) orbiting at $26.0^{+19.0}_{-11.0}$ au. This detection makes HIP 9618 one of only five bright (K < 8 mag) transiting multiplanet systems known to host a planet with P > 50 d, opening the door for the atmospheric characterization of warm (Teq < 750 K) sub-Neptunes.
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