A reactive transport model was developed to simulate reaction of carbonates within a pore network for the high‐pressure CO2‐acidified conditions relevant to geological carbon sequestration. The pore ...network was based on a synthetic oolithic dolostone. Simulation results produced insights that can inform continuum‐scale models regarding reaction‐induced changes in permeability and porosity. As expected, permeability increased extensively with dissolution caused by high concentrations of carbonic acid, but neither pH nor calcite saturation state alone was a good predictor of the effects, as may sometimes be the case. Complex temporal evolutions of interstitial brine chemistry and network structure led to the counterintuitive finding that a far‐from‐equilibrium solution produced less permeability change than a nearer‐to‐equilibrium solution at the same pH. This was explained by the pH buffering that increased carbonate ion concentration and inhibited further reaction. Simulations of different flow conditions produced a nonunique set of permeability‐porosity relationships. Diffusive‐dominated systems caused dissolution to be localized near the inlet, leading to substantial porosity change but relatively small permeability change. For the same extent of porosity change caused from advective transport, the domain changed uniformly, leading to a large permeability change. Regarding precipitation, permeability changes happen much slower compared to dissolution‐induced changes and small amounts of precipitation, even if located only near the inlet, can lead to large changes in permeability. Exponent values for a power law that relates changes in permeability and porosity ranged from 2 to 10, but a value of 6 held constant when conditions led to uniform changes throughout the domain.
Key Points
Acid dissolves carbonates but neither pH nor saturation alone predicts extent
Dissolution increases porosity but permeability increase depends on flow rate
Permeability decreases due to precipitation but effects are localized
The relative impact of center volume and of surgeon volume on early outcomes after the arterial switch operation (ASO) is incompletely understood.
Neonates in the Society of Thoracic Surgeons ...Congenital Heart Surgery Database (2005-2012) undergoing ASO for transposition of the great arteries were included in the analysis. Multivariable logistic regression with adjustment for patient factors and ventricular septal defect closure was used to evaluate relationships between annual center and surgeon volume and a composite end point (in-hospital mortality or major complications).
The study included 2,357 patients (84 centers, 155 surgeons). Median annual ASO center volume was 4 (range, 1 to 18). Median annual surgeon volume was 2 (range, 0.1 to 11). In-hospital mortality was 3.4%; 14.7% had major morbidity and 15.5% met the composite end point. Analyzed individually, lower center and surgeon volumes were each associated with the composite end point (odds ratios for centers with 2 versus 10 cases/y, 1.92; 95% confidence interval, 1.23 to 2.99); odds ratios for surgeons with 1 versus 6 cases/y, 2.16; 95% confidence interval, 1.42 to 3.26). When analyzed together, the addition of surgeon volume to the center volume models attenuated but did not completely mitigate the association of center volume with outcome (relative attenuation of odds ratio = 31%). Addition of center volume to surgeon volume models attenuated the association of surgeon volume with outcome to a lesser degree (relative attenuation of odds ratio = 11%).
Center and surgeon volume each influence early outcomes after ASO; however, surgeon volume appears to play a more prominent role. Surgeon and center ASO volume should be considered in the context of initiatives to improve outcomes from ASO for transposition of the great arteries.
Protein digestion is a key challenge in mass spectrometry (MS)-based structural proteomics. Although using hydrogen–deuterium exchange kinetics with MS (HDX-MS) to interrogate the high-order ...structure of proteins is now established, it can be challenging for β-barrel proteins, which are important in cellular transport. These proteins contain a continuous chain of H-bonds that impart stability, causing difficulty in digestion for bottom-up measurements. To overcome this impediment, we tested organic solvents as denaturants during on-line pepsin digestion of soluble β-barrel proteins. We selected green fluorescent protein (GFP), siderocalin (Scn), and retinol-binding protein 4 (RBP4) as model proteins and screened six different polar-aprotic and polar-protic solvent combinations to disrupt the H-bonds and hydrophobic interactions holding together the β-sheets. The use of organic solvents improves digestion, generating more peptides from the rigid β-barrel regions, without compromising the ability to predict the retinol binding site on RBP4 when adopting this proteolysis with HDX.
Alpha-emitters are radionuclides that decay through the emission of high linear energy transfer α-particles and possess favorable pharmacologic profiles for cancer treatment. When coupled with ...monoclonal antibodies, peptides, small molecules, or nanoparticles, the excellent cytotoxic capability of α-particle emissions has generated a strong interest in exploring targeted α-therapy in the pre-clinical setting and more recently in clinical trials in oncology. Multiple obstacles have been overcome by researchers and clinicians to accelerate the development of targeted α-therapies, especially with the recent improvement in isotope production and purification, but also with the development of innovative strategies for optimized targeting. Numerous studies have demonstrated the in vitro and in vivo efficacy of the targeted α-therapy. Radium-223 (
223
Ra) dichloride (Xofigo®) is the first α-emitter to have received FDA approval for the treatment of prostate cancer with metastatic bone lesions. There is a significant increase in the number of clinical trials in oncology using several radionuclides such as Actinium-225 (
225
Ac), Bismuth-213 (
213
Bi), Lead-212 (
212
Pb), Astatine (
211
At) or Radium-223 (
223
Ra) assessing their safety and preliminary activity. This review will cover their therapeutic application as well as summarize the investigations that provide the foundation for further clinical development.
The Wee1 (WEE1hu) inhibitor adavosertib and gemcitabine have shown preclinical synergy and promising activity in early phase clinical trials. We aimed to determine the efficacy of this combination in ...patients with ovarian cancer.
In this double-blind, randomised, placebo-controlled, phase 2 trial, women with measurable recurrent platinum-resistant or platinum-refractory high-grade serous ovarian cancer were recruited from 11 academic centres in the USA and Canada. Women were eligible if they were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0–2, a life expectancy of more than 3 months, and normal organ and marrow function. Women with ovarian cancer of non-high-grade serous histology were eligible for enrolment in a non-randomised exploratory cohort. Eligible participants with high-grade serous ovarian cancer were randomly assigned (2:1), using block randomisation (block size of three and six) and no stratification, to receive intravenous gemcitabine (1000 mg/m2 on days 1, 8, and 15) with either oral adavosertib (175 mg) or identical placebo once daily on days 1, 2, 8, 9, 15, and 16, in 28-day cycles until disease progression or unacceptable toxicity. Patients and the team caring for each patient were masked to treatment assignment. The primary endpoint was progression-free survival. The safety and efficacy analysis population comprised all patients who received at least one dose of treatment. The trial is registered with ClinicalTrials.gov, NCT02151292, and is closed to accrual.
Between Sept 22, 2014, and May 30, 2018, 124 women were enrolled, of whom 99 had high-grade serous ovarian cancer and were randomly assigned to adavosertib plus gemcitabine (65 66%) or placebo plus gemcitabine (34 34%). 25 women with non-high-grade serous ovarian cancer were enrolled in the exploratory cohort. After randomisation, five patients with high-grade serous ovarian cancer were found to be ineligible (four in the experimental group and one in the control group) and did not receive treatment. Median age for all treated patients (n=119) was 62 years (IQR 54–67). Progression-free survival was longer with adavosertib plus gemcitabine (median 4·6 months 95% CI 3·6–6·4 with adavosertib plus gemcitabine vs 3·0 months 1·8–3·8 with placebo plus gemcitabine; hazard ratio 0·55 95% CI 0·35–0·90; log-rank p=0·015). The most frequent grade 3 or worse adverse events were haematological (neutropenia in 38 62% of 61 participants in the adavosertib plus gemcitabine group vs ten 30% of 33 in the placebo plus gemcitabine group; thrombocytopenia in 19 31% of 61 in the adavosertib plus gemcitabine group vs two 6% of 33 in the placebo plus gemcitabine group). There were no treatment-related deaths; two patients (one in each group in the high-grade serous ovarian cancer cohort) died while on study medication (from sepsis in the experimental group and from disease progression in the control group).
The observed clinical efficacy of a Wee1 inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress. This therapeutic approach might be applicable to other tumour types with high replication stress; larger confirmatory studies are required.
US National Cancer Institute Cancer Therapy Evaluation Program, Ontario Institute for Cancer Research, US Department of Defense, Princess Margaret Cancer Foundation, and AstraZeneca.
The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical ...phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.
Atlantic tropical cyclone activity, as measured by annual storm counts, reached anomalous levels over the past decade. The short nature of the historical record and potential issues with its ...reliability in earlier decades, however, has prompted an ongoing debate regarding the reality and significance of the recent rise. Here we place recent activity in a longer-term context by comparing two independent estimates of tropical cyclone activity over the past 1,500 years. The first estimate is based on a composite of regional sedimentary evidence of landfalling hurricanes, while the second estimate uses a previously published statistical model of Atlantic tropical cyclone activity driven by proxy reconstructions of past climate changes. Both approaches yield consistent evidence of a peak in Atlantic tropical cyclone activity during medieval times (around ad 1000) followed by a subsequent lull in activity. The statistical model indicates that the medieval peak, which rivals or even exceeds (within uncertainties) recent levels of activity, results from the reinforcing effects of La-Niña-like climate conditions and relative tropical Atlantic warmth.
Over the past eight hundred thousand years, glacial-interglacial cycles oscillated with a period of one hundred thousand years ('100k world'
). Ice core and ocean sediment data have shown that ...atmospheric carbon dioxide, Antarctic temperature, deep ocean temperature, and global ice volume correlated strongly with each other in the 100k world
. Between about 2.8 and 1.2 million years ago, glacial cycles were smaller in magnitude and shorter in duration ('40k world'
). Proxy data from deep-sea sediments suggest that the variability of atmospheric carbon dioxide in the 40k world was also lower than in the 100k world
, but we do not have direct observations of atmospheric greenhouse gases from this period. Here we report the recovery of stratigraphically discontinuous ice more than two million years old from the Allan Hills Blue Ice Area, East Antarctica. Concentrations of carbon dioxide and methane in ice core samples older than two million years have been altered by respiration, but some younger samples are pristine. The recovered ice cores extend direct observations of atmospheric carbon dioxide, methane, and Antarctic temperature (based on the deuterium/hydrogen isotope ratio δD
, a proxy for regional temperature) into the 40k world. All climate properties before eight hundred thousand years ago fall within the envelope of observations from continuous deep Antarctic ice cores that characterize the 100k world. However, the lowest measured carbon dioxide and methane concentrations and Antarctic temperature in the 40k world are well above glacial values from the past eight hundred thousand years. Our results confirm that the amplitudes of glacial-interglacial variations in atmospheric greenhouse gases and Antarctic climate were reduced in the 40k world, and that the transition from the 40k to the 100k world was accompanied by a decline in minimum carbon dioxide concentrations during glacial maxima.
New tools for monitoring and manipulating neural activity have been developed with steadily improving functionality, specificity, and reliability, which are critical both for mapping neural circuits ...and treating neurological diseases. This review focuses on the use of an invertebrate animal, the marine mollusk
, in the development of novel neurotechniques. We review the basic physiological properties of
neurons and discuss the specific aspects that make it advantageous for developing novel neural interfaces: First,
nerves consist only of unmyelinated axons with various diameters, providing a particularly useful model of the unmyelinated C fibers in vertebrates that are known to carry important sensory information, including those that signal pain. Second,
neural tissues can last for a long period in an
experimental setup. This allows comprehensive tests such as the exploration of parameter space on the same nerve to avoid variability between animals and minimize animal use. Third, nerves in large
can be many centimeters in length, making it possible to easily discriminate axons with different diameters based on their conduction velocities.
nerves are a particularly good approximation of the unmyelinated C fibers, which are hard to stimulate, record, and differentiate from other nerve fibers in vertebrate animal models using epineural electrodes. Fourth, neurons in
are large, uniquely identifiable, and electrically compact. For decades, researchers have used
for the development of many novel neurotechnologies. Examples include high-frequency alternating current (HFAC), focused ultrasound (FUS), optical neural stimulation, recording, and inhibition, microelectrode arrays, diamond electrodes, carbon fiber microelectrodes, microscopic magnetic stimulation and magnetic resonance electrical impedance tomography (MREIT). We also review a specific example that illustrates the power of
for accelerating technology development: selective infrared neural inhibition of small-diameter unmyelinated axons, which may lead to a translationally useful treatment in the future. Generally,
is suitable for testing modalities whose mechanism involves basic biophysics that is likely to be similar across species. As a tractable experimental system,
can help the rapid development of novel neuromodulation technologies.
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