Reprint of “Pharmacokinetic modelling of the anti-malarial drug artesunate and its active metabolite dihydroartemisinin”

A four compartment mechanistic mathematical model is developed for the pharmacokinetics of the commonly used anti-malarial drug artesunate and its principle metabolite dihydroartemisinin following oral administration of artesunate. The model is structurally unidentifiable unless additional constraints are imposed. Combinations of mechanistically derived constraints are considered to assess their effects on structural identifiability and on model fits. Certain combinations of the constraints give rise to locally or globally identifiable model structures. Initial validation of the model under various combinations of the constraints leading to identifiable model structures was performed against a dataset of artesunate and dihydroartemisinin concentration–time profiles of 19 malaria patients. When all the discussed constraints were imposed on the model, the resulting globally identifiable model structure was found to fit reasonably well to those patients with normal drug absorption profiles. However, there is wide variability in the fitted parameters and further investigation is warranted

Clinical Feasibility of Noninvasive Visualization of Lymphatic Flow with Principles of Spin Labeling MR Imaging: Implications for Lymphedema Assessment

Purpose To extend a commonly used noninvasive arterial spin labeling magnetic resonance (MR) imaging method for measuring blood flow to evaluate lymphatic flow. Materials and Methods All volunteers (n = 12) provided informed consent in accordance with institutional review board and HIPAA regulations. Quantitative relaxation time (T1 and T2) measurements were made in extracted human lymphatic fluid at 3.0 T. Guided by these parameters, an arterial spin labeling MR imaging approach was adapted to measure lymphatic flow (flow-alternating inversion-recovery lymphatic water labeling, 3 × 3 × 5 mm) in healthy subjects (n = 6; mean age, 30 years ± 1 [standard deviation]; recruitment duration, 2 months). Lymphatic flow velocity was quantified by performing spin labeling measurements as a function of postlabeling delay time and by measuring time to peak signal intensity in axillary lymph nodes. Clinical feasibility was evaluated in patients with stage II lymphedema (three women; age range, 43–64 years) and in control subjects with unilateral cuff-induced lymphatic stenosis (one woman, two men; age range, 31–35 years). Results Mean T1 and T2 relaxation times of lymphatic fluid at 3.0 T were 3100 msec ± 160 (range, 2930–3210 msec; median, 3200 msec) and 610 msec ± 12 (range, 598–618 msec; median, 610 msec), respectively. Healthy lymphatic flow (afferent vessel to axillary node) velocity was 0.61 cm/min ± 0.13 (n = 6). A reduction (P \u3c .005) in lymphatic flow velocity in the affected arms of patients and the affected arms of healthy subjects with manipulated cuff-induced flow reduction was observed. The ratio of unaffected to affected axilla lymphatic velocity (1.24 ± 0.18) was significantly (P \u3c .005) higher than the left-to-right ratio in healthy subjects (0.91 ± 0.18). Conclusion This work provides a foundation for clinical investigations whereby lymphedema etiogenesis and therapies may be interrogated without exogenous agents and with clinically available imaging equipment

Pericyte heterogeneity identified by 3D ultrastructural analysis of the microvessel wall

Confident identification of pericytes (PCs) remains an obstacle in the field, as a single molecular marker for these unique perivascular cells remains elusive. Adding to this challenge is the recent appreciation that PC populations may be heterogeneous, displaying a range of morphologies within capillary networks. We found additional support on the ultrastructural level for the classification of these PC subtypes—“thin-strand” (TSP), mesh (MP), and ensheathing (EP)—based on distinct morphological characteristics. Interestingly, we also found several examples of another cell type, likely a vascular smooth muscle cell, in a medial layer between endothelial cells (ECs) and pericytes (PCs) harboring characteristics of the ensheathing type. A conserved feature across the different PC subtypes was the presence of extracellular matrix (ECM) surrounding the vascular unit and distributed in between neighboring cells. The thickness of this vascular basement membrane was remarkably consistent depending on its location, but never strayed beyond a range of 150–300 nm unless thinned to facilitate closer proximity of neighboring cells (suggesting direct contact). The density of PC-EC contact points (“peg-and-socket” structures) was another distinguishing feature across the different PC subtypes, as were the apparent contact locations between vascular cells and brain parenchymal cells. In addition to this thinning, the extracellular matrix (ECM) surrounding EPs displayed another unique configuration in the form of extensions that emitted out radially into the surrounding parenchyma. Knowledge of the origin and function of these structures is still emerging, but their appearance suggests the potential for being mechanical elements and/or perhaps signaling nodes via embedded molecular cues. Overall, this unique ultrastructural perspective provides new insights into PC heterogeneity and the presence of medial cells within the microvessel wall, the consideration of extracellular matrix (ECM) coverage as another PC identification criteria, and unique extracellular matrix (ECM) configurations (i.e., radial extensions) that may reveal additional aspects of PC heterogeneity

Quantification of finger grasps during activities of daily life using convolutional neural networks : a pilot study

Quantifying finger kinematics can improve the authors’ understanding of finger function and facilitate the design of efficient prosthetic devices while also identifying movement disorders and assessing the impact of rehabilitation interventions. Here, the authors present a study that quantifies grasps depicted in taxonomies during selected Activities of Daily Living (ADL). A single participant held a series of standard objects using specific grasps which were used to train Convolutional Neural Networks (CNN) for each of the four fingers individually. The experiment also recorded hand manipulation of objects during ADL. Each set of ADL finger kinematic data was tested using the trained CNN, which identified and quantified the grasps required to accomplish each task. Certain grasps appeared more often depending on the finger studied, meaning that even though there are physiological interdependencies, fingers have a certain degree of autonomy in performing dexterity tasks. The identified and most frequent grasps agreed with the previously reported findings, but also highlighted that an individual might have specific dexterity needs which may vary with profession and age. The proposed method can be used to identify and quantify key grasps for finger/hand prostheses, to provide a more efficient solution that is practical in their day-to-day tasks

Pharmacokinetic modelling of the anti-malarial drug artesunate and its active metabolite dihydroartemisinin

A four compartment mechanistic mathematical model is developed for the pharmacokinetics of the commonly used anti-malarial drug artesunate and its principle metabolite dihydroartemisinin following oral administration of artesunate. The model is structurally unidentifiable unless additional constraints are imposed. Combinations of mechanistically derived constraints are considered to assess their effects on structural identifiability and on model fits. Certain combinations of the constraints give rise to locally or globally identifiable model structures. Initial validation of the model under various combinations of the constraints leading to identifiable model structures was performed against a dataset of artesunate and dihydroartemisinin concentration–time profiles of 19 malaria patients. When all the discussed constraints were imposed on the model, the resulting globally identifiable model structure was found to fit reasonably well to those patients with normal drug absorption profiles. However, there is wide variability in the fitted parameters and further investigation is warranted

Minimising soil organic carbon erosion by wind is critical for land degradation neutrality

The Land Degradation-Neutrality (LDN) framework of the United Nations Convention to Combat Desertification (UNCCD) is underpinned by three complementary interactive indicators (metrics: vegetation cover, net primary productivity; NPP and soil organic carbon; SOC) as proxies for change in land-based natural capital. The LDN framework assumes that SOC changes slowly primarily by decomposition and respiration of CO2 to the atmosphere. However, there is growing evidence that soil erosion by wind, water and tillage also reduces SOC stocks rapidly after land use and cover change. Here we modify a physically-based sediment transport model to estimate wind erosion and better represent the vegetation cover (using land surface aerodynamic roughness; that is the plant canopy coverage, stone cover, soil aggregates, etc. that protects the soil surface from wind erosion) and quantify the contribution of wind erosion to global SOC erosion (2001-2016). We use the wind erosion model to identify global dryland regions where SOC erosion by wind may be a significant problem for achieving LDN. Selected sites in global drylands show SOC erosion by wind accelerating over time. Without targeting and reducing SOC erosion, management practices in these regions will fail to sequester SOC and reduce land degradation. We describe the interrelated nature of the LDN indicators, the importance of including SOC erosion by wind erosion and how by explicitly accounting for wind erosion processes, we can better represent the physical effects of changing land cover on land degradation. Our results for Earth’s drylands show that modelling SOC stock reduction by wind erosion is better than using land cover and SOC independently. Furthermore, emphasising the role of wind erosion in UNCCD and Intergovernmental Panel on Climate Change (IPCC) reporting will better support LDN and climate change mitigation and adaptation globall

Poloidal asymmetries in edge transport barriers

Measurements of impurities in Alcator C-Mod indicate that in the pedestal region, significant poloidal asymmetries can exist in the impurity density, ion temperature, and main ion density. In light of the observation that ion temperature and electrostatic potential are not constant on a flux surface [Theiler et al., Nucl. Fusion 54, 083017 (2014)], a technique based on total pressure conservation to align profiles measured at separate poloidal locations is presented and applied. Gyrokinetic neoclassical simulations with XGCa support the observed large poloidal variations in ion temperature and density, and that the total pressure is approximately constant on a flux surface. With the updated alignment technique, the observed in-out asymmetry in impurity density is reduced from previous publishing [Churchill et al., Nucl. Fusion 53, 122002 (2013)], but remains substantial (nz,H/nz,L∼6). Candidate asymmetry drivers are explored, showing that neither non-uniform impurity sources nor localized fluctuation-driven transport are able to explain satisfactorily the impurity density asymmetry. Since impurity density asymmetries are only present in plasmas with strong electron density gradients, and radial transport timescales become comparable to parallel transport timescales in the pedestal region, it is suggested that global transport effects relating to the strong electron density gradients in the pedestal are the main driver for the pedestal in-out impurity density asymmetry.United States. Department of Energy (DE-FC02-99ER54512)United States. Department of Energy (DE-FG02-06ER54845)United States. Department of Energy (DE-FG02-86ER53223)United States. Department of Energy (DE-AC02-09CH11466

Willpower Satisficing

Satisficing Consequentialism is often rejected as hopeless. Perhaps its greatest problem is that it risks condoning the gratuitous prevention of goodness above the baseline of what qualifies as “good enough”. I propose a radical new willpower-based version of the view that avoids this problem, and that better fits with the motivation of avoiding an excessively demanding conception of morality. I further demonstrate how, by drawing on the resources of an independent theory of blameworthiness, we may obtain a principled specification of what counts as “good enough”

Immuno-Molecular Targeted Therapy Use and Survival Benefit in Patients with Stage IVB Cervical Carcinoma in Commission on Cancer

PURPOSE: To investigate IMT use and survival in real-world stage IVB cervical cancer patients outside randomized clinical trials. METHODS: Patients diagnosed with stage IVB cervical cancer during 2013-2019 in the National Cancer Database and treated with chemotherapy (CT) ± external beam radiation (EBRT) ± intracavitary brachytherapy (ICBT) ± IMT were studied. The adjusted hazard ratio (AHR) and 95% confidence interval (CI) for risk of death were estimated in patients treated with vs. without IMT after applying propensity score analysis to balance the clinical covariates. RESULTS: There were 3164 evaluable patients, including 969 (31%) who were treated with IMT. The use of IMT increased from 11% in 2013 to 46% in 2019. Age, insurance, facility type, sites of distant metastasis, and type of first-line treatment were independently associated with using IMT. In propensity-score-balanced patients, the median survival was 18.6 vs. 13.1 months for with vs. without IMT ( CONCLUSIONS: IMT was associated with a consistent survival benefit in real-world patients with stage IVB cervical cancer

Survival disparities in non-Hispanic Black and White cervical cancer patients vary by histology and are largely explained by modifiable factors

PurposeWe investigated racial disparities in survival by histology in cervical cancer and examined the factors contributing to these disparities.MethodsNon-Hispanic Black and non-Hispanic White (hereafter known as Black and White) patients with stage I-IV cervical carcinoma diagnosed between 2004 and 2017 in the National Cancer Database were studied. Survival differences were compared using Cox modeling to estimate hazard ratio (HR) or adjusted HR (AHR) and 95% confidence interval (CI). The contribution of demographic, socioeconomic and clinical factors to the Black vs White differences in survival was estimated after applying propensity score weighting in patients with squamous cell carcinoma (SCC) or adenocarcinoma (AC).ResultsThis study included 10,111 Black and 43,252 White patients with cervical cancer. Black patients had worse survival than White cervical cancer patients (HR = 1.40, 95% CI = 1.35-1.45). Survival disparities between Black and White patients varied significantly by histology (HR = 1.20, 95% CI = 1.15-1.24 for SCC; HR = 2.32, 95% CI = 2.12-2.54 for AC, interaction p < 0.0001). After balancing the selected demographic, socioeconomic and clinical factors, survival in Black vs. White patients was no longer different in those with SCC (AHR = 1.01, 95% CI 0.97-1.06) or AC (AHR = 1.09, 95% CI = 0.96-1.24). In SCC, the largest contributors to survival disparities were neighborhood income and insurance. In AC, age was the most significant contributor followed by neighborhood income, insurance, and stage. Diagnosis of AC (but not SCC) at ≥65 years old was more common in Black vs. White patients (26% vs. 13%, respectively).ConclusionsHistology matters in survival disparities and diagnosis at ≥65 years old between Black and White cervical cancer patients. These disparities were largely explained by modifiable factors