Virtual Patient Simulation Using Copula Modeling.

Virtual patient simulation is increasingly performed to support model-based optimization of clinical trial designs or individualized dosing strategies. Quantitative pharmacological models typically incorporate individual-level patient characteristics, or covariates, which enable the generation of virtual patient cohorts. The individual-level patient characteristics, or covariates, used as input for such simulations should accurately reflect the values seen in real patient populations. Current methods often make unrealistic assumptions about the correlation between patient's covariates or require direct access to actual data sets with individual-level patient data, which may often be limited by data sharing limitations. We propose and evaluate the use of copulas to address current shortcomings in simulation of patient-associated covariates for virtual patient simulations for model-based dose and trial optimization in clinical pharmacology. Copulas are multivariate distribution functions that can capture joint distributions, including the correlation, of covariate sets. We compare the performance of copulas to alternative simulation strategies, and we demonstrate their utility in several case studies. Our work demonstrates that copulas can reproduce realistic patient characteristics, both in terms of individual covariates and the dependence structure between different covariates, outperforming alternative methods, in particular when aiming to reproduce high-dimensional covariate sets. In conclusion, copulas represent a versatile and generalizable approach for virtual patient simulation which preserve relationships between covariates, and offer an open science strategy to facilitate re-use of patient data sets.

Ocean warming drives rapid dynamic activation of marine-terminating glacier on the west Antarctic Peninsula.

Ice dynamic change is the primary cause of mass loss from the Antarctic Ice Sheet, thus it is important to understand the processes driving ice-ocean interactions and the timescale on which major change can occur. Here we use satellite observations to measure a rapid increase in speed and collapse of the ice shelf fronting Cadman Glacier in the absence of surface meltwater ponding. Between November 2018 and December 2019 ice speed increased by 94 ± 4% (1.47 ± 0.6 km/yr), ice discharge increased by 0.52 ± 0.21 Gt/yr, and the calving front retreated by 8 km with dynamic thinning on grounded ice of 20.1 ± 2.6 m/yr. This change was concurrent with a positive temperature anomaly in the upper ocean, where a 400 m deep channel allowed warm water to reach Cadman Glacier driving the dynamic activation, while neighbouring Funk and Lever Glaciers were protected by bathymetric sills across their fjords. Our results show that forcing by warm ocean water can cause the rapid onset of dynamic imbalance and increased ice discharge from glaciers on the Antarctic Peninsula, highlighting the region's sensitivity to future climate variability.

Annual mass budget of Antarctic ice shelves from 1997 to 2021.

Antarctic ice shelves moderate the contribution of the Antarctic Ice Sheet to global sea level rise; however, ice shelf health remains poorly constrained. Here, we present the annual mass budget of all Antarctic ice shelves from 1997 to 2021. Out of 162 ice shelves, 71 lost mass, 29 gained mass, and 62 did not change mass significantly. Of the shelves that lost mass, 68 had statistically significant negative mass trends, 48 lost more than 30% of their initial mass, and basal melting was the dominant contributor to that mass loss at a majority (68%). At many ice shelves, mass losses due to basal melting or iceberg calving were significantly positively correlated with grounding line discharge anomalies; however, the strength and form of this relationship varied substantially between ice shelves. Our results illustrate the utility of partitioning high-resolution ice shelf mass balance observations into its components to quantify the contributors to ice shelf mass change and the response of grounded ice.

Widespread increase in dynamic imbalance in the Getz region of Antarctica from 1994 to 2018.

The Getz region of West Antarctica is losing ice at an increasing rate; however, the forcing mechanisms remain unclear. Here we use satellite observations and an ice sheet model to measure the change in ice speed and mass balance of the drainage basin over the last 25-years. Our results show a mean increase in speed of 23.8 % between 1994 and 2018, with three glaciers accelerating by over 44 %. Speedup across the Getz basin is linear, with speedup and thinning directly correlated confirming the presence of dynamic imbalance. Since 1994, 315 Gt of ice has been lost contributing 0.9 ± 0.6 mm global mean sea level, with increased loss since 2010 caused by a snowfall reduction. Overall, dynamic imbalance accounts for two thirds of the mass loss from this region of West Antarctica over the past 25-years, with a longer-term response to ocean forcing the likely driving mechanism.

Damage accelerates ice shelf instability and mass loss in Amundsen Sea Embayment.

Pine Island Glacier and Thwaites Glacier in the Amundsen Sea Embayment are among the fastest changing outlet glaciers in West Antarctica with large consequences for global sea level. Yet, assessing how much and how fast both glaciers will weaken if these changes continue remains a major uncertainty as many of the processes that control their ice shelf weakening and grounding line retreat are not well understood. Here, we combine multisource satellite imagery with modeling to uncover the rapid development of damage areas in the shear zones of Pine Island and Thwaites ice shelves. These damage areas consist of highly crevassed areas and open fractures and are first signs that the shear zones of both ice shelves have structurally weakened over the past decade. Idealized model results reveal moreover that the damage initiates a feedback process where initial ice shelf weakening triggers the development of damage in their shear zones, which results in further speedup, shearing, and weakening, hence promoting additional damage development. This damage feedback potentially preconditions these ice shelves for disintegration and enhances grounding line retreat. The results of this study suggest that damage feedback processes are key to future ice shelf stability, grounding line retreat, and sea level contributions from Antarctica. Moreover, they underline the need for incorporating these feedback processes, which are currently not accounted for in most ice sheet models, to improve sea level rise projections.

Oropharyngeal HPV Detection Techniques in HPV-associated Head and Neck Cancer Patients.

BACKGROUND/AIM: The incidence of human papilloma virus (HPV)-related head and neck squamous cell carcinoma (HNSCC) has been increasing in the last decades. Analysis of oral brushing or rinsing samples for screening or stratification could potentially improve screening and prevention. PATIENTS AND METHODS: Oral brushes and mouthwashes were taken from 20 patients with HPV-associated HNSCC before definite therapy. HPV genotyping was performed for the detection of 14 high-risk HPV subtypes and correlated to DNA isolated from tumor tissue. RESULTS: Ten of 20 patients were tested HPV positive by using either method. There was a significant correlation between macroscopic visibility of tumor and positive HPV detection (p<0.001) and HPV detection and tumor size (p<0.001). HPV was detected in all macroscopically visible tumors. Half of the HPV cases who had macroscopically invisible tumors were missed by both methods. CONCLUSION: Both techniques are limited in the detection of macroscopically non-visible and small tumors. Therefore, the application of these techniques for screening or diagnosis of HNSCC is not recommended.

Barium isotope fractionation during the experimental transformation of aragonite to witherite and of gypsum to barite, and the effect of ion (de)solvation.

In this study, we present the experimental results for stable barium (Ba) isotope fractionation (137Ba/134Ba) during the transformation of aragonite (CaCO3) and gypsum (CaSO4·2H2O) in Ba-bearing aqueous solution to witherite (BaCO3) and barite (BaSO4), respectively. The process was studied at three temperatures between 4 and 60 °C. In all cases, the transformation leads to a relative enrichment of the lighter 134Ba isotope in the solid compared to the aqueous solution, with 137/134Ba enrichment factors between -0.11 and -0.17 ‰ for BaCO3, and -0.21 and -0.26 ‰ for BaSO4. The corresponding mass-dependent 138/134Ba enrichment factors are -0.15 to -0.23 ‰ for BaCO3, and -0.28 to -0.35 ‰ for BaSO4. The magnitude of isotope fractionation is within the range of recent reports for witherite and barite formation, as well as trace Ba incorporation into orthorhombic aragonite, and no substantial impact of temperature can be found between 4 and 80 °C. In previous studies, ion (de)solvation has been suggested to impact both the crystallization process of Ba-bearing solids and associated Ba isotope fractionation. Precipitation experiments of BaSO4 and BaCO3 using an methanol-containing aqueous solution indicate only a minor effect of ion and crystal surface (de)solvation on the overall Ba isotope fractionation process.

Barium isotope fractionation during experimental formation of the double carbonate BaMn[CO3](2) at ambient temperature.

In this study, we present the first experimental results for stable barium (Ba) isotope ((137)Ba/(134)Ba) fractionation during low-temperature formation of the anhydrous double carbonate BaMn[CO(3)](2). This investigation is part of an ongoing work on Ba fractionation in the natural barium cycle. Precipitation at a temperature of 21±1°C leads to an enrichment of the lighter Ba isotope described by an enrichment factor of-0.11±0.06‰ in the double carbonate than in an aqueous barium-manganese(II) chloride/sodium bicarbonate solution, which is within the range of previous reports for synthetic pure BaCO (3) (witherite) formation.

Hydrogen sulphide release to surface waters at the Precambrian/Cambrian boundary.

Animal-like multicellular fossils appeared towards the end of the Precambrian, followed by a rapid increase in the abundance and diversity of fossils during the Early Cambrian period, an event also known as the 'Cambrian explosion'. Changes in the environmental conditions at the Precambrian/Cambrian transition (about 542 Myr ago) have been suggested as a possible explanation for this event, but are still a matter of debate. Here we report molybdenum isotope signatures of black shales from two stratigraphically correlated sample sets with a depositional age of around 542 Myr. We find a transient molybdenum isotope signal immediately after the Precambrian/Cambrian transition. Using a box model of the oceanic molybdenum cycle, we find that intense upwelling of hydrogen sulphide-rich deep ocean water best explains the observed Early Cambrian molybdenum isotope signal. Our findings suggest that the Early Cambrian animal radiation may have been triggered by a major change in ocean circulation, terminating a long period during which the Proterozoic ocean was stratified, with sulphidic deep water.

Combined chemical separation of Lu, Hf, Sm, Nd, and Rees from a single rock digest: precise and accurate isotope determinations of Lu-Hf and Sm-Nd using multicollector-ICPMS.

A combined procedure for separating Lu, Hf, Sm, Nd, and rare earth elements (REEs) from a single sample digest is presented. The procedure consists of the following five steps: (1) sample dissolution via sodium peroxide sintering; (2) separation of the high field strength elements from the REEs and other matrix elements by a HF-free anion-exchange column procedure; (3) purification of Hf on a cation-exchange resin; (4) separation of REEs from other matrix elements by cation exchange; (5) Lu, Sm, and Nd separation from the other REEs by reversed-phase ion chromatography. Analytical reproducibilities of Sm-Nd and Lu-Hf isotope systematics are demonstrated for standard solutions and international rock reference materials. Results show overall good reproducibilities for Sm-Nd systematics independent of the rock type analyzed. For the Lu-Hf systematics, the reproducibility of the parent/daughter ratio is much better for JB-1 (basalt) than for two analyzed felsic crustal rocks (DR-N and an Archaean granitoid). It is demonstrated that this poorer reproducibility of the Lu/Hf ratio is truly caused by sample heterogeneity; thus, results are geologically reasonable.