2,838 research outputs found
Effectiveness of durvalumab versus chemotherapy in metastatic urothelial cancer: an observational, indirect comparison
Aim: To compare the overall survival of patients with metastatic urothelial carcinoma (mUC) who failed platinum-based chemotherapy and received durvalumab or chemotherapy. / Patients & methods: In an indirect comparison of patients with mUC who failed platinum-based chemotherapy, those who received durvalumab in a single-arm study were matched to patients from the Flatiron oncology electronic medical record database who received chemotherapy (n = 158 for each cohort). Matching was based on propensity scores. Kaplan–Meier methods and Cox regression models were utilized. / Results: Median overall survival was 11.2 months (95% CI: 7.2–16.9) for durvalumab versus 8.2 months (95% CI: 6.7–9.8) for chemotherapy (hazard ratio: 0.63; 95% CI: 0.48–0.84). / Conclusion: As a second-line therapy for mUC, durvalumab was associated with longer overall survival than chemotherapy
Evidence for Anthropogenic Surface Loading as Trigger Mechanism of the 2008 Wenchuan Earthquake
Two and a half years prior to China's M7.9 Wenchuan earthquake of May 2008,
at least 300 million metric tons of water accumulated with additional seasonal
water level changes in the Minjiang River Valley at the eastern margin of the
Longmen Shan. This article shows that static surface loading in the Zipingpu
water reservoir induced Coulomb failure stresses on the nearby Beichuan thrust
fault system at <17km depth. Triggering stresses exceeded levels of daily lunar
and solar tides and perturbed a fault area measuring 416+/-96km^2. These stress
perturbations, in turn, likely advanced the clock of the mainshock and directed
the initial rupture propagation upward towards the reservoir on the
"Coulomb-like" Beichuan fault with rate-and-state dependent frictional
behavior. Static triggering perturbations produced up to 60 years (0.6%) of
equivalent tectonic loading, and show strong correlations to the coseismic
slip. Moreover, correlations between clock advancement and coseismic slip,
observed during the mainshock beneath the reservoir, are strongest for a longer
seismic cycle (10kyr) of M>7 earthquakes. Finally, the daily event rate of the
micro-seismicity (M>0.5) correlates well with the static stress perturbations,
indicating destabilization.Comment: 22 pages, 4 figures, 3 table
Diminished temperature and vegetation seasonality over northern high latitudes
Global temperature is increasing, especially over northern lands (>50° N), owing to positive feedbacks1. As this increase is most pronounced in winter, temperature seasonality (ST)—conventionally defined as the difference between summer and winter temperatures—is diminishing over time2, a phenomenon that is analogous to its equatorward decline at an annual scale. The initiation, termination and performance of vegetation photosynthetic activity are tied to threshold temperatures3. Trends in the timing of these thresholds and cumulative temperatures above them may alter vegetation productivity, or modify vegetation seasonality (SV), over time. The relationship between ST and SV is critically examined here with newly improved ground and satellite data sets. The observed diminishment of ST and SV is equivalent to 4° and 7° (5° and 6°) latitudinal shift equatorward during the past 30 years in the Arctic (boreal) region. Analysis of simulations from 17 state-of-the-art climate models4 indicates an additional STdiminishment equivalent to a 20° equatorward shift could occur this century. How SV will change in response to such large projected ST declines and the impact this will have on ecosystem services5 are not well understood. Hence the need for continued monitoring6 of northern lands as their seasonal temperature profiles evolve to resemble thosefurther south.Lopullinen vertaisarvioitu käsikirjoitu
Anaesthesia for serial whole-lung lavage in a patient with severe pulmonary alveolar proteinosis: a case report
<p>Abstract</p> <p>Introduction</p> <p>Pulmonary alveolar proteinosis is a rare condition that requires treatment by whole-lung lavage. We report a case of severe pulmonary alveolar proteinosis and discuss a safe and effective strategy for the anaesthetic management of patients undergoing this complex procedure.</p> <p>Case presentation</p> <p>A 34-year-old Caucasian man was diagnosed with severe pulmonary alveolar proteinosis. He developed severe respiratory failure and subsequently underwent serial whole-lung lavage. Our anaesthetic technique included the use of pre-oxygenation, complete lung separation with a left-sided double-lumen endotracheal tube, one-lung ventilation with positive end-expiratory pressure, appropriate ventilatory monitoring, cautious use of positional manoeuvres and single-lumen endotracheal tube exchange for short-term postoperative ventilation.</p> <p>Conclusion</p> <p>Patients with pulmonary alveolar proteinosis may present with severe respiratory failure and require urgent whole-lung lavage. We have described a safe and effective strategy for anaesthesia for whole-lung lavage. We recommend our anaesthetic technique for patients undergoing this complex and uncommon procedure.</p
Direct Measurement of Perchlorate Exposure Biomarkers in a Highly Exposed Population: A Pilot Study
Exposure to perchlorate is ubiquitous in the United States and has been found to
be widespread in food and drinking water. People living in the lower Colorado
River region may have perchlorate exposure because of perchlorate in ground
water and locally-grown produce. Relatively high doses of perchlorate can
inhibit iodine uptake and impair thyroid function, and thus could impair
neurological development in utero. We examined human exposures to perchlorate in
the Imperial Valley among individuals consuming locally grown produce and
compared perchlorate exposure doses to state and federal reference doses. We
collected 24-hour urine specimen from a convenience sample of 31 individuals and
measured urinary excretion rates of perchlorate, thiocyanate, nitrate, and
iodide. In addition, drinking water and local produce were also sampled for
perchlorate. All but two of the water samples tested negative for perchlorate.
Perchlorate levels in 79 produce samples ranged from non-detect to 1816 ppb.
Estimated perchlorate doses ranged from 0.02 to 0.51 µg/kg of body
weight/day. Perchlorate dose increased with the number of servings of dairy
products consumed and with estimated perchlorate levels in produce consumed. The
geometric mean perchlorate dose was 70% higher than for the NHANES
reference population. Our sample of 31 Imperial Valley residents had higher
perchlorate dose levels compared with national reference ranges. Although none
of our exposure estimates exceeded the U. S. EPA reference dose, three
participants exceeded the acceptable daily dose as defined by bench mark dose
methods used by the California Office of Environmental Health Hazard
Assessment
Nonthermal Emission from Star-Forming Galaxies
The detections of high-energy gamma-ray emission from the nearby starburst
galaxies M82 & NGC253, and other local group galaxies, broaden our knowledge of
star-driven nonthermal processes and phenomena in non-AGN star-forming
galaxies. We review basic aspects of the related processes and their modeling
in starburst galaxies. Since these processes involve both energetic electrons
and protons accelerated by SN shocks, their respective radiative yields can be
used to explore the SN-particle-radiation connection. Specifically, the
relation between SN activity, energetic particles, and their radiative yields,
is assessed through respective measures of the particle energy density in
several star-forming galaxies. The deduced energy densities range from O(0.1)
eV/cm^3 in very quiet environments to O(100) eV/cm^3 in regions with very high
star-formation rates.Comment: 17 pages, 5 figures, to be published in Astrophysics and Space
Science Proceeding
Properties of small molecular drug loading and diffusion in a fluorinated PEG hydrogel studied by ^1H molecular diffusion NMR and ^(19)F spin diffusion NMR
R_f-PEG (fluoroalkyl double-ended poly(ethylene glycol)) hydrogel is potentially useful as a drug delivery depot due to its advanced properties of sol–gel two-phase coexistence and low surface erosion. In this study, ^1H molecular diffusion nuclear magnetic resonance (NMR) and ^(19)F spin diffusion NMR were used to probe the drug loading and diffusion properties of the R_f-PEG hydrogel for small anticancer drugs, 5-fluorouracil (FU) and its hydrophobic analog, 1,3-dimethyl-5-fluorouracil (DMFU). It was found that FU has a larger apparent diffusion coefficient than that of DMFU, and the diffusion of the latter was more hindered. The result of ^(19)F spin diffusion NMR for the corresponding freeze-dried samples indicates that a larger portion of DMFU resided in the R_f core/IPDU intermediate-layer region (where IPDU refers to isophorone diurethane, as a linker to interconnect the R_f group and the PEG chain) than that of FU while the opposite is true in the PEG–water phase. To understand the experimental data, a diffusion model was proposed to include: (1) hindered diffusion of the drug molecules in the R_f core/IPDU-intermediate-layer region; (2) relatively free diffusion of the drug molecules in the PEG-water phase (or region); and (3) diffusive exchange of the probe molecules between the above two regions. This study also shows that molecular diffusion NMR combined with spin diffusion NMR is useful in studying the drug loading and diffusion properties in hydrogels for the purpose of drug delivery applications
A Tunable Two-impurity Kondo system in an atomic point contact
Two magnetic atoms, one attached to the tip of a Scanning Tunneling
Microscope (STM) and one adsorbed on a metal surface, each constituting a Kondo
system, have been proposed as one of the simplest conceivable systems
potentially exhibiting quantum critical behaviour. We have succeeded in
implementing this concept experimentally for cobalt dimers clamped between an
STM tip and a gold surface. Control of the tip-sample distance with
sub-picometer resolution allows us to tune the interaction between the two
cobalt atoms with unprecedented precision. Electronic transport measurements on
this two-impurity Kondo system reveal a rich physical scenario which is
governed by a crossover from local Kondo screening to non-local singlet
formation due to antiferromagnetic coupling as a function of separation of the
cobalt atoms.Comment: 22 pages, 5 figure
Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome
A novel microduplication syndrome involving various-sized contiguous duplications in 17p13.3 has recently been described, suggesting that increased copy number of genes in 17p13.3, particularly PAFAH1B1, is associated with clinical features including facial dysmorphism, developmental delay, and autism spectrum disorder. We have previously shown that patient-derived cell lines from individuals with haploinsufficiency of RPA1, a gene within 17p13.3, exhibit an impaired ATR-dependent DNA damage response (DDR). Here, we show that cell lines from patients with duplications specifically incorporating RPA1 exhibit a different although characteristic spectrum of DDR defects including abnormal S phase distribution, attenuated DNA double strand break (DSB)-induced RAD51 chromatin retention, elevated genomic instability, and increased sensitivity to DNA damaging agents. Using controlled conditional over-expression of RPA1 in a human model cell system, we also see attenuated DSB-induced RAD51 chromatin retention. Furthermore, we find that transient over-expression of RPA1 can impact on homologous recombination (HR) pathways following DSB formation, favouring engagement in aberrant forms of recombination and repair. Our data identifies unanticipated defects in the DDR associated with duplications in 17p13.3 in humans involving modest RPA1 over-expression
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