The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved ...progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX.
Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression.
In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib,n = 64; crizotinib,n = 58), 43 had measurable lesions (alectinib,n = 21; crizotinib,n = 22), and 46 had received prior radiotherapy (alectinib,n = 25; crizotinib,n = 21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25–0.64 and those without (HR 0.51, 95% CI: 0.33–0.80,P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P < 0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy and 78.6% versus 40.0%, respectively, in those who had not.
Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advancedALK+ NSCLC, irrespective of prior CNS disease or radiotherapy.
ClinicalTrials.gov NCT02075840
Cloud droplet relative dispersion, defined as the standard deviation over the mean cloud droplet size, is of central importance in determining and understanding aerosol indirect effects. In recent ...work, it was found that cloud droplet size distributions become broader as a result of supersaturation variability and that the sensitivity of this effect is inversely related to cloud droplet number density. The subject is investigated in further detail using an extensive dataset from a laboratory cloud chamber capable of producing steady-state turbulence. An extended stochastic theory is found to successfully describe properties of the droplet size distribution, including an analytical expression for the relative dispersion. The latter is found to depend on the cloud droplet removal time, which in turn increases with the cloud droplet number density. The results show that relative dispersion decreases monotonically with increasing droplet number density, consistent with some recent atmospheric observations. Experiments spanning fast to slow microphysics regimes are reported. The observed dispersion is used to estimate time scales for autoconversion, demonstrating the important role of the turbulence-induced broadening effect on precipitation development. An initial effort is made to extend the stochastic theory to an atmospheric context with a steady updraft, for which autoconversion time is the controlling factor for droplet lifetime. As in the cloud chamber, relative dispersion is found to increase with decreasing cloud droplet number density.
Unraveling the macroevolutionary history of bryophytes, which arose soon after the origin of land plants but exhibit substantially lower species richness than the more recently derived angiosperms, ...has been challenged by the scarce fossil record. Here we demonstrate that overall estimates of net species diversification are approximately half those reported in ferns and ∼30% those described for angiosperms. Nevertheless, statistical rate analyses on time-calibrated large-scale phylogenies reveal that mosses and liverworts underwent bursts of diversification since the mid-Mesozoic. The diversification rates further increase in specific lineages towards the Cenozoic to reach, in the most recently derived lineages, values that are comparable to those reported in angiosperms. This suggests that low diversification rates do not fully account for current patterns of bryophyte species richness, and we hypothesize that, as in gymnosperms, the low extant bryophyte species richness also results from massive extinctions.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein acquired a D614G mutation early in the pandemic that confers greater infectivity and is now the globally dominant form. ...To determine whether D614G might also mediate neutralization escape that could compromise vaccine efficacy, sera from spike-immunized mice, nonhuman primates, and humans were evaluated for neutralization of pseudoviruses bearing either D614 or G614 spike. In all cases, the G614 pseudovirus was moderately more susceptible to neutralization. The G614 pseudovirus also was more susceptible to neutralization by receptor-binding domain (RBD) monoclonal antibodies and convalescent sera from people infected with either form of the virus. Negative stain electron microscopy revealed a higher percentage of the 1-RBD “up” conformation in the G614 spike, suggesting increased epitope exposure as a mechanism of enhanced vulnerability to neutralization. Based on these findings, the D614G mutation is not expected to be an obstacle for current vaccine development.
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•Spike-based SARS-CoV-2 vaccines potently neutralize the globally dominant G614 variant•Vaccinated and immune sera neutralize G614 better than the original spike•The structure of the G614 spike demonstrates a more open position of the RBD
Serum from SARS-CoV-2 spike-vaccinated mice, NHPs and humans, and convalescent patients, along with receptor-binding domain (RBD)-specific monoclonal antibodies neutralize the widespread G614-containing virus at greater levels than the original D614 version. Structural data demonstrate that the G614 spike is in a more open conformation with extended RBDs.
Circulating tumour cells (CTCs) are the precursor cells for the formation of metastatic disease. With a simple blood draw, liquid biopsies enable the non-invasive sampling of CTCs from the blood, ...which have the potential to provide important insights into cancer detection and monitoring. Since gaining FDA approval in 2004, the CellSearch system has been used to determine the prognosis of patients with metastatic breast, prostate and colorectal cancers. This utilises the cell surface marker Epithelial Cell Adhesion Molecule (EpCAM), to enrich CTCs, and many other technologies have adopted this approach. More recently, the role of mesenchymal-like CTCs in metastasis formation has come to light. It has been suggested that these cells are more aggressive metastatic precursors than their epithelial counterparts; however, mesenchymal CTCs remain undetected by EpCAM-based enrichment methods. This has prompted the development of a variety of 'label free' enrichment technologies, which exploit the unique physical properties of CTCs (such as size and deformability) compared to other blood components. Here, we review a wide range of both immunocapture and label free CTC enrichment technologies, summarising the most significant advantages and disadvantages of each. We also highlight the important characteristics that technologies should possess for routine clinical use, since future developments could have important clinical implications, with the potential to direct personalised therapies for patients with cancer.
Zonal-mean or basin-mean analyses often conclude that the midlatitude circulation will undergo a poleward shift with global warming. In this study, the models from phase 5 of the Coupled Model ...Intercomparison Project are used to provide a detailed examination of midlatitude circulation change as a function of longitude and season. The two-dimensional vertically integrated momentum budget is used to identify the dominant terms that maintain the anomalous surface wind stress, thereby allowing a distinction between features that are maintained by high-frequency eddies and those that involve changes in the lower-frequency or stationary flow.
Early examples of computers were almost exclusively based on mechanical devices. Although electronic computers became dominant in the past 60 years, recent advancements in three-dimensional ...micro-additive manufacturing technology provide new fabrication techniques for complex microstructures which have rekindled research interest in mechanical computations. Here we propose a new digital mechanical computation approach based on additively-manufacturable micro-mechanical logic gates. The proposed mechanical logic gates (i.e., NOT, AND, OR, NAND, and NOR gates) utilize multi-stable micro-flexures that buckle to perform Boolean computations based purely on mechanical forces and displacements with no electronic components. A key benefit of the proposed approach is that such systems can be additively fabricated as embedded parts of microarchitected metamaterials that are capable of interacting mechanically with their surrounding environment while processing and storing digital data internally without requiring electric power.
The process of Electrocoagulation (EC), the in-situ production of coagulants by passing an electric current through sacrificial electrodes, is free of chemical additives and cost-effective. This ...makes it the most widely used water and wastewater treatment method. However, the literature highlights some significant drawbacks of this method including EC unit design limitations. This research therefore aimed to develop a new EC unit design using drilled plates (electrodes) to mix the solution being treated without using external mixers, this minimising power consumption. The performance of the new EC unit was validated by applying it to remove iron from water taking into account the effects of applied current density (ACD), the pH of the water (PoW), iron concentration (IC) and treatment time (TT). The effects of these parameters were optimised using the Box-Behnken model. Synthetic water samples containing different concentrations of iron (10-30 mg/l), were treated in a continuous flow, using the new EC reactor at different ACD (1.5–4.5 mA/cm2), PoW (4–10) and TT (10–50 min). The results revealed that the removal of 99.9% of iron was achieved by keeping PoW, ACD, IC and TT at 7, 3 mA/cm2, 10 mg/l and 50 min, respectively. The effects of ACD, POW, IC and TT on iron removal could be successfully simulated with R2 = 0.9788. The cost of removing iron using the proposed EC unit was 0.623 £/m3.
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•The new EC reactor removed 99.9% of 30 mg/l of iron.•The performance of the new unit was modelled with R2 of 0.9788.•The new EC reactor reduced the need for external mixing devices.•The operating cost for the iron removal using the proposed EC unit was 0.623 £/m3.
Background
The objective of this systematic review and meta‐analysis was to assess the relationship between the chloride content of intravenous resuscitation fluids and patient outcomes in the ...perioperative or intensive care setting.
Methods
Systematic searches were performed of PubMed/MEDLINE, Embase and Cochrane Library (CENTRAL) databases in accordance with PRISMA guidelines. Randomized clinical trials, controlled clinical trials and observational studies were included if they compared outcomes in acutely ill or surgical patients receiving either high‐chloride (ion concentration greater than 111 mmol/l up to and including 154 mmol/l) or lower‐chloride (concentration 111 mmol/l or less) crystalloids for resuscitation. Endpoints examined were mortality, measures of kidney function, serum chloride, hyperchloraemia/metabolic acidosis, blood transfusion volume, mechanical ventilation time, and length of hospital and intensive care unit stay. Risk ratios (RRs), mean differences (MDs) or standardized mean differences (SMDs) and confidence intervals were calculated using fixed‐effect modelling.
Results
The search identified 21 studies involving 6253 patients. High‐chloride fluids did not affect mortality but were associated with a significantly higher risk of acute kidney injury (RR 1·64, 95 per cent c.i. 1·27 to 2·13; P < 0·001) and hyperchloraemia/metabolic acidosis (RR 2·87, 1·95 to 4·21; P < 0·001). High‐chloride fluids were also associated with greater serum chloride (MD 3·70 (95 per cent c.i. 3·36 to 4·04) mmol/l; P < 0·001), blood transfusion volume (SMD 0·35, 0·07 to 0·63; P = 0·014) and mechanical ventilation time (SMD 0·15, 0·08 to 0·23; P < 0·001). Sensitivity analyses excluding heavily weighted studies resulted in non‐statistically significant effects for acute kidney injury and mechanical ventilation time.
Conclusion
A weak but significant association between higher chloride content fluids and unfavourable outcomes was found, but mortality was unaffected by chloride content.
Chloride associated with morbidity but not mortality
Redox-active self-assembled monolayers (SAMs) provide an excellent platform for investigating electron transfer kinetics. Using a well-defined bridge, a redox center can be positioned at a fixed ...distance from the electrode and electron transfer kinetics probed using a variety of electrochemical techniques. Cyclic voltammetry, AC voltammetry, electrochemical impedance spectroscopy, and chronoamperometry are most commonly used to determine the rate of electron transfer of redox-activated SAMs. A variety of redox species have been attached to SAMs, and include transition metal complexes (e.g., ferrocene, ruthenium pentaammine, osmium bisbipyridine, metal clusters) and organic molecules (e.g., galvinol, C
60). SAMs offer an ideal environment to study the outer-sphere interactions of redox species. The composition and integrity of the monolayer and the electrode material influence the electron transfer kinetics and can be investigated using electrochemical methods. Theoretical models have been developed for investigating SAM structure. This review discusses methods and monolayer compositions for electrochemical measurements of redox-active SAMs.
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