Category: Nevin Manimala

PLoS Comput Biol. 2022 Jul 22;18(7):e1009996. doi: 10.1371/journal.pcbi.1009996. eCollection 2022 Jul.

ABSTRACT

Collateral circulation in the circle of Willis (CoW), closely associated with disease mechanisms and treatment outcomes, can be effectively investigated using one-dimensional-zero-dimensional hemodynamic simulations. As the entire cardiovascular system is considered in the simulation, it captures the systemic effects of local arterial changes, thus reproducing collateral circulation that reflects biological phenomena. The simulation facilitates rapid assessment of clinically relevant hemodynamic quantities under patient-specific conditions by incorporating clinical data. During patient-specific simulations, the impact of clinical data uncertainty on the simulated quantities should be quantified to obtain reliable results. However, as uncertainty quantification (UQ) is time-consuming and computationally expensive, its implementation in time-sensitive clinical applications is considered impractical. Therefore, we constructed a surrogate model based on machine learning using simulation data. The model accurately predicts the flow rate and pressure in the CoW in a few milliseconds. This reduced computation time enables the UQ execution with 100 000 predictions in a few minutes on a single CPU core and in less than a minute on a GPU. We performed UQ to predict the risk of cerebral hyperperfusion (CH), a life-threatening condition that can occur after carotid artery stenosis surgery if collateral circulation fails to function appropriately. We predicted the statistics of the postoperative flow rate increase in the CoW, which is a measure of CH, considering the uncertainties of arterial diameters, stenosis parameters, and flow rates measured using the patients’ clinical data. A sensitivity analysis was performed to clarify the impact of each uncertain parameter on the flow rate increase. Results indicated that CH occurred when two conditions were satisfied simultaneously: severe stenosis and when arteries of small diameter serve as the collateral pathway to the cerebral artery on the stenosis side. These findings elucidate the biological aspects of cerebral circulation in terms of the relationship between collateral flow and CH.

PMID:35867968 | DOI:10.1371/journal.pcbi.1009996

Blood Coagul Fibrinolysis. 2022 Jul 22. doi: 10.1097/MBC.0000000000001152. Online ahead of print.

ABSTRACT

Bleeding disorders are causes of great concern and panic for parents and primary care providers. Lack of knowledge and awareness on appropriate screening tests and factor product preparation contributed to potential diagnostic delays, increased complications, and economic costs. This study aimed to determine and compare the approach of primary care physicians (including general practitioners) and emergency physicians with a questionnaire including simulation-based cases on hemophilia. This simulation and two-stage questionnaire study was conducted with 244 participants. Before-after questionnaires, two case simulations, a brief presentation, and statistical analysis were performed. Participants mostly preferred tests, such as prothrombin time (PT) or partial thromboplastin time (PTT) to bleeding time for primary hemostasis (PT/PTT n: 192, 84.2%, bleeding time n: 94, 41.2%). Similar results were found for secondary hemostasis (bleeding time n: 144, 63.4%). There was a lack of knowledge in the management of simulation-based cases of acute hemorrhagic complications and factor product preparation (complication case: correct n: 100, 55.2%; initial doses correct n: 56, 43.4%, factor preparing correct n: 37, 49.3%, factor admission correct n: 36, 24.3%). All changed significantly, after the presentation (P = 0.000). Our study shows that there is probably a lack of knowledge of diagnostic investigations and appropriate factor product preparation with possible consequences for patients and economics.

PMID:35867946 | DOI:10.1097/MBC.0000000000001152

Blood Coagul Fibrinolysis. 2022 Jul 22. doi: 10.1097/MBC.0000000000001153. Online ahead of print.

ABSTRACT

Thromboprophylaxis is the cornerstone strategy for thrombotic antiphospholipid syndrome (APS). Data comparing direct oral anticoagulants (DOACs) to Vitamin K antagonists (VKAs) in the secondary prevention of thrombosis in APS patients remain contentious. We aim to review and analyse literature on the efficacy and safety of DOACs compared with VKAs in treating patients with APS. A literature search was performed from inception to 31 December 2021. Subgroups were analysed based on the risk stratification of APS profiles and different DOAC types. A total of nine studies with 1131 patients were included in the meta-analysis. High-risk APS patients (triple positive APS) who used DOACs displayed an increased risk of recurrent thrombosis [risk ratio = 3.65, 95% confidence interval (95% CI): 1.49-8.93; I2 = 29%, P = 0.005] compared with those taking VKAs. Similar risk of recurrent thrombosis or major bleeding was noted in low-risk APS patients (single or double antibody-positive) upon administering DOACs or VKAs. The utilization of Rivaroxaban was associated with a high risk of recurrent thromboses (RR = 2.63; 95% CI: 1.56-4.42; I2 = 0, P = 0.0003), particularly recurrent arterial thromboses (RR = 4.52; 95% CI: 1.99-10.29; I2 = 0, P = 0.18) in overall APS patients. Comparisons of the rate of recurrent thrombosis events and major bleeding events when using dabigatran or apixaban versus VKAs yielded no statistical differences. In the absence of contraindications, this meta-analysis suggests that VKAs remain the first-choice treatment for high-risk APS patients, with DOACs a more appropriate option for low-risk APS patients. Different DOACs may exhibit different levels of efficacy and safety for thromboprophylaxis in APS patients and require further exploration.

PMID:35867933 | DOI:10.1097/MBC.0000000000001153

Anal Chem. 2022 Jul 22. doi: 10.1021/acs.analchem.2c00611. Online ahead of print.

ABSTRACT

Adulteration of medications is an emerging and significant threat to human health and well-being, even though adulterants are still often not considered seriously in clinical or forensic toxicology. Screening of drug adulterations is a major challenge and concern for regulatory authorities worldwide. Metformin hydrochloride, an important drug to treat diabetes, is found to be adulterated worldwide and a major reason to worry about the health and safety procedure. We have demonstrated a first-of-a-kind electrochemical biomedical device utilizing exfoliated graphene oxide (GO)─Nafion-modified customized gold screen-printed electrodes (spiral electrochemical notification-coupled electrode, SENCE), driven by electrochemical adsorptive stripping voltammetry, to identify the trace level adulteration in metformin. The GO-Nafion-SPE interface has been characterized by powder X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, energy-dispersive X-ray analysis, and Fourier transform infrared. Custom-made screen-printed SENCEs have been functionalized with GO nanoparticles (transducer) to obtain a fingerprint signal response of metformin using differential pulse voltammetry. A linear calibrated dose response has been obtained with n = 3 repetitions with a low limit of detection of 10 ppm for metformin. We have used the sensing response as a function of adulteration, and it is extensively supported by rigorous statistical analysis along with the help of the machine learning tool. This is a first-of-its-kind IoT-enabled electrochemical sensor and analysis platform that can detect drug adulteration as a low, medium, and high output.

PMID:35867902 | DOI:10.1021/acs.analchem.2c00611

Bioconjug Chem. 2022 Jul 22. doi: 10.1021/acs.bioconjchem.2c00152. Online ahead of print.

ABSTRACT

Cell penetrating peptides conjugated to delivery vehicles, such as nanoparticles or antibodies, can enhance the cytosolic delivery of macromolecules. The present study examines the effects of conjugation to cell penetrating and endosomal escape peptides (i.e., TAT, GALA, and H6CM18) on the pharmacokinetics and distribution of an anti-carcinoembryonic antigen “catch-and-release” monoclonal antibody, 10H6, in a murine model of colorectal cancer. GALA and TAT were conjugated to 10H6 using SoluLINK technology that allowed the evaluation of peptide-to-antibody ratio by ultraviolet spectroscopy. H6CM18 was conjugated to either NHS or maleimide-modified 10H6 using an azide-modified valine-citrulline linker and copper-free click chemistry. Unmodified and peptide-conjugated 10H6 preparations were administered intravenously at 6.67 nmol/kg to mice-bearing MC38^CEA+ tumors. Unconjugated 10H6 demonstrated a clearance of 19.9 ± 1.36 mL/day/kg, with an apparent volume of distribution of 62.4 ± 7.78 mL/kg. All antibody-peptide conjugates exhibited significantly decreased plasma and tissue exposure, increased plasma clearance, and increased distribution volume. Examination of tissue-to-plasma exposure ratios showed an enhanced selectivity of 10H6-TAT for the GI tract (+25%), kidney (+24%), liver (+38%), muscle (+3%), and spleen (+33%). 10H6-GALA and 10H6-H6CM18 conjugates demonstrated decreased exposure in all tissues, relative to unmodified 10H6. All conjugates demonstrated decreased tumor exposure and selectivity; however, differences in tumor selectivity between 10H6 and 10H6-H6CM18 (maleimide) were not statistically significant. Relationships between the predicted peptide conjugate isoelectric point (pI) and pharmacokinetic parameters were bell-shaped, where pI values around 6.8-7 exhibit the slowest plasma clearance and smallest distribution volume. The data and analyses presented in this work may guide future efforts to develop immunoconjugates with cell penetrating and endosomal escape peptides.

PMID:35867869 | DOI:10.1021/acs.bioconjchem.2c00152

Metallomics. 2022 Jul 22:mfac052. doi: 10.1093/mtomcs/mfac052. Online ahead of print.

ABSTRACT

Breast cancer is the leading cause of cancer death and tremendous efforts are undertaken to limit dissemination and to provide effective treatment. Various histopathological parameters are routinely assessed in breast cancer biopsies to provide valuable diagnostic and prognostic information. MMP-11 and CD45 are tumour associated antigens and potentially valuable biomarkers for grading aggressiveness and metastatic probability. This paper presents methods for quantitative and multiplexed imaging of MMP-11 and CD45 in breast cancer tissues and investigates their potential for improved cancer characterisation and patient stratification. An immunohistochemistry (IHC)-assisted LA-ICP-MS method was successfully developed and optimised using lanthanide tagged monoclonal antibodies as proxies to determine spatial distributions and concentrations of the two breast cancer biomarkers. The labelling degree of antibodies was determined via size exclusion-inductively coupled plasma-tandem mass spectrometry (SEC-ICP-MS/MS) employing on-line calibration via post-column isotope dilution analysis. The calibration of spatial distributions of labelled lanthanides in tissues was performed by ablating mould prepared gelatine standards spiked with element standards. Knowledge of labelling degrees enabled the translation of lanthanide concentrations into biomarkers concentrations. k-means clustering was used to select tissue areas for statistical analysis and mean concentrations were compared for sets of metastatic, non-metastatic and healthy samples. MMP-11 was expressed in stroma surrounding tumour areas, while CD45 was predominantly found inside tumour areas of high cell density. There was no significant correlation between CD45 and metastasis (p = 0.70), however, MMP-11 was significantly upregulated (202%) in metastatic samples compared to non-metastatic (p = 0.0077) and healthy tissues (p = 0.0087).

PMID:35867868 | DOI:10.1093/mtomcs/mfac052

ALTEX. 2022 Jul 15. doi: 10.14573/altex.2205081. Online ahead of print.

ABSTRACT

New approach methodologies (NAMs) are in vitro, in chemico, and in silico or computational approaches that can potentially be used to reduce animal testing. For NAMs that require laboratory experiments, it is critical that they provide consistent and reliable results. While guidance has been provided on improving the reproducibility of NAMs that require laboratory experiments, there is not yet an overarching technical framework that details how to add measurement quality features into a protocol. In this manuscript, we discuss such a framework and provide a step-by step process describing how to refine a protocol using basic quality tools. The steps in this framework include 1) conceptual analysis of sources of technical variability in the assay, 2) within laboratory evaluation of assay performance, 3) statistical data analysis, and 4) determination of method transferability (if needed). While each of these steps has discrete components, they are all inter-related and insights from any step can influence the others. Following the steps in this framework can help reveal the advantages and limitations of different choices during the design of an assay such as which in-process control measurements to include and how many replicates to use for each control measurement and for each test substance. Overall, the use of this technical framework can support optimizing NAM reproducibility, thereby supporting meeting research and regulatory needs.

PMID:35867862 | DOI:10.14573/altex.2205081

J Infect Dis. 2022 Jul 22:jiac311. doi: 10.1093/infdis/jiac311. Online ahead of print.

ABSTRACT

BACKGROUND: A novel human parechovirus 3 Australian recombinant (HPeV3-AR) strain emerged in 2013 and coincided with biennial outbreaks of sepsis-like illnesses in infants. We evaluated the molecular evolution of the HPeV-AR strain and its association with severe HPeV infections.

METHODS: HPeV3-positive samples collected from hospitalized infants aged 5-252 days in two Australian states (2013-2020) and from a community-based birth cohort (2010-2014) were sequenced. Coding regions were used to conduct phylogenetic and evolutionary analyses. A recombinant-specific PCR was designed and utilized to screen all clinical and community HPeV3-positive samples.

RESULTS: Complete coding regions of 54 cases were obtained, which showed the HPeV3-AR strain progressively evolving, particularly in the 3′ end of the non-structural genes. The HPeV3-AR strain was not detected in the community birth cohort until the initial outbreak in late 2013. High-throughput screening showed most (>75%) hospitalized HPeV3 cases involved the AR strain in the first three clinical outbreaks, with declining prevalence in the 2019-20 season. The AR strain was not statistically associated with increased clinical severity amongst hospitalised infants.

DISCUSSION: The HPeV3-AR was the dominant strain during the study period. Increased hospital admissions may have been from a temporary fitness advantage and/or increased virulence.

PMID:35867852 | DOI:10.1093/infdis/jiac311

J Chem Inf Model. 2022 Jul 22. doi: 10.1021/acs.jcim.2c00258. Online ahead of print.

ABSTRACT

Selecting the most appropriate compounds to synthesize and test is a vital aspect of drug discovery. Methods like clustering and diversity present weaknesses in selecting the optimal sets for information gain. Active learning techniques often rely on an initial model and computationally expensive semi-supervised batch selection. Herein, we describe a new subset-based selection method, Coverage Score, that combines Bayesian statistics and information entropy to balance representation and diversity to select a maximally informative subset. Coverage Score can be influenced by prior selections and desirable properties. In this paper, subsets selected through Coverage Score are compared against subsets selected through model-independent and model-dependent techniques for several datasets. In drug-like chemical space, Coverage Score consistently selects subsets that lead to more accurate predictions compared to other selection methods. Subsets selected through Coverage Score produced Random Forest models that have a root-mean-square-error up to 12.8% lower than subsets selected at random and can retain up to 99% of the structural dissimilarity of a diversity selection.

PMID:35867814 | DOI:10.1021/acs.jcim.2c00258

Proc Natl Acad Sci U S A. 2022 Jul 12;119(28):e2204761119. doi: 10.1073/pnas.2204761119. Epub 2022 Jul 7.

ABSTRACT

It is established that changes in sea level influence melt production at midocean ridges, but whether changes in melt production influence the pattern of bathymetry flanking midocean ridges has been debated on both theoretical and empirical grounds. To explore the dynamics that may give rise to a sea-level influence on bathymetry, we simulate abyssal hills using a faulting model with periodic variations in melt supply. For 100-ky melt-supply cycles, model results show that faults initiate during periods of amagmatic spreading at half-rates >2.3 cm/y and for 41-ky melt-supply cycles at half-rates >3.8 cm/y. Analysis of bathymetry across 17 midocean ridge regions shows characteristic wavelengths that closely align with the predictions from the faulting model. At intermediate-spreading ridges (half-rates >2.3 cm/y and [Formula: see text]3.8 cm/y) abyssal hill spacing increases with spreading rate at 0.99 km/(cm/y) or 99 ky (n [Formula: see text] 12; 95% CI, 87 to 110 ky), and at fast-spreading ridges (half-rates >3.8 cm/y) spacing increases at 38 ky (n [Formula: see text] 5; 95% CI, 29 to 47 ky). Including previously published analyses of abyssal-hill spacing gives a more precise alignment with the primary periods of Pleistocene sea-level variability. Furthermore, analysis of bathymetry from fast-spreading ridges shows a highly statistically significant spectral peak (P < 0.01) at the 1/(41-ky) period of Earth’s variations in axial tilt. Faulting models and observations both support a linkage between glacially induced sea-level change and the fabric of the sea floor over the late Pleistocene.

PMID:35867751 | DOI:10.1073/pnas.2204761119