Evaluating the impact of anatomical and physiological variability on human equivalent doses using PBPK models.

Addressing human anatomical and physiological variability is a crucial component of human health risk assessment of chemicals. Experts have recommended probabilistic chemical risk assessment paradigms in which distributional adjustment factors are used to account for various sources of uncertainty and variability, including variability in the pharmacokinetic behavior of a given substance in different humans. In practice, convenient assumptions about the distribution forms of adjustment factors and human equivalent doses (HEDs) are often used. Parameters such as tissue volumes and blood flows are likewise often assumed to be lognormally or normally distributed without evaluating empirical data for consistency with these forms. In this work, we performed dosimetric extrapolations using physiologically based pharmacokinetic (PBPK) models for dichloromethane (DCM) and chloroform that incorporate uncertainty and variability to determine if the HEDs associated with such extrapolations are approximately lognormal and how they depend on the underlying distribution shapes chosen to represent model parameters. We accounted for uncertainty and variability in PBPK model parameters by randomly drawing their values from a variety of distribution types. We then performed reverse dosimetry to calculate HEDs based on animal points of departure (PODs) for each set of sampled parameters. Corresponding samples of HEDs were tested to determine the impact of input parameter distributions on their central tendencies, extreme percentiles, and degree of conformance to lognormality. This work demonstrates that the measurable attributes of human variability should be considered more carefully and that generalized assumptions about parameter distribution shapes may lead to inaccurate estimates of extreme percentiles of HEDs.

Radiomics analysis of ultrasound images to discriminate between benign and malignant adnexal masses with solid ultrasound morphology.

OBJECTIVE: Our primary aim was to identify radiomic ultrasound features that can distinguish benign from malignant adnexal masses with solid ultrasound morphology, and primary invasive from metastatic solid ovarian masses, and to develop ultrasound-based machine learning models that include radiomics features to discriminate between benign and malignant solid adnexal masses. Our secondary aim was to compare the diagnostic performance of our radiomics models with that of the ADNEX model and subjective assessment by an experienced ultrasound examiner. METHODS: This is a retrospective observational single center study. Patients with a histological diagnosis of an adnexal tumor with solid morphology at preoperative ultrasound examination performed between 2014 and 2021 were included. The patient cohort was split into training and validation sets with a ratio of 70:30 and with the same proportion of benign and malignant (borderline, primary invasive and metastatic) tumors in the two subsets. The extracted radiomic features belonged to two different families: intensity-based statistical features and textural features. Models to predict malignancy were built based on a random forest classifier, fine-tuned using 5-fold cross-validation over the training set, and tested on the held-out validation set. The variables used in model building were patient's age, and those radiomic features that were statistically significantly different between benign and malignant adnexal masses (Wilcoxon-Mann-Whitney Test with Benjamini-Hochberg correction for multiple comparisons) and assessed as not redundant based on the Pearson correlation coefficient. We describe discriminative ability as area under the receiver operating characteristics curve (AUC) and classification performance as sensitivity and specificity. RESULTS: 326 patients were identified and 775 preoperative ultrasound images were analyzed. 68 radiomic features were extracted, 52 differed statistically significantly between benign and malignant tumors in the training set, and 18 features were selected for inclusion in model building. The same 52 radiomic features differed statistically significantly between benign, primary invasive malignant and metastatic tumors. However, the values of the features manifested overlap between primary malignant and metastatic tumors and did not differ statistically significantly between them. In the validation set, 25/98 tumors (25.5%) were benign, 73/98 (74.5%) were malignant (6 borderline, 57 primary invasive, 10 metastases). In the validation set, a model including only radiomics features had an AUC of 0.80, and 78% sensitivity and 76% specificity at its optimal risk of malignancy cutoff (68% based on Youden's index). The corresponding results for a model including age and radiomics features were 0.79, 86% and 56% (cutoff 60% based on Youden's method), while those of the ADNEX model were 0.88, 99% and 64% (at 20% malignancy cutoff). Subjective assessment had sensitivity 99% and specificity 72%. CONCLUSIONS: Even though our radiomics models had discriminative ability inferior to that of the ADNEX model, our results are promising enough to justify continued development of radiomics analysis of ultrasound images of adnexal masses. This article is protected by copyright. All rights reserved.

Ancestral sequence reconstruction of Mic60 reveals a residue signature supporting respiration in yeast.

In eukaryotes, the essential process of cellular respiration takes place in the cristae of mitochondria. The protein Mic60 is known to stabilize crista junctions; however, how the C-terminal Mitofilin domain of Mic60 mediates cristae-supported respiration remains elusive. Here, we used ancestral sequence reconstruction to generate Mitofilin ancestors up to and including the last opisthokont common ancestor (LOCA). We found that yeast-lineage derived Mitofilin ancestors as far back as the LOCA rescue respiration. By comparing Mitofilin ancestors with different respiratory phenotypes, we identify four residues that explain the difference between respiration functional yeast- and non-functional animal-derived common Mitofilin ancestors. Our results imply that Mitofilin-supported respiration in yeast stems from a conserved mechanism, and provide a foundation for investigating the divergence of candidate crista junction interactions present during the emergence of eukaryotes.

An all-inclusive model for predicting invasive bacterial infection in febrile infants age 7-60 days.

BACKGROUND: Invasive bacterial infections (IBIs) in febrile infants are rare but potentially devastating. We aimed to derive and validate a predictive model for IBI among febrile infants age 7-60 days. METHODS: Data were abstracted retrospectively from electronic records of 37 emergency departments (EDs) for infants with a measured temperature >=100.4 F who underwent an ED evaluation with blood and urine cultures. Models to predict IBI were developed and validated respectively using a random 80/20 dataset split, including 10-fold cross-validation. We used precision recall curves as the classification metric. RESULTS: Of 4411 eligible infants with a mean age of 37 days, 29% had characteristics that would likely have excluded them from existing risk stratification protocols. There were 196 patients with IBI (4.4%), including 43 (1.0%) with bacterial meningitis. Analytic approaches varied in performance characteristics (precision recall range 0.04-0.29, area under the curve range 0.5-0.84), with the XGBoost model demonstrating the best performance (0.29, 0.84). The five most important variables were serum white blood count, maximum temperature, absolute neutrophil count, absolute band count, and age in days. CONCLUSION: A machine learning model (XGBoost) demonstrated the best performance in predicting a rare outcome among febrile infants, including those excluded from existing algorithms. IMPACT: Several models for the risk stratification of febrile infants have been developed. There is a need for a preferred comprehensive model free from limitations and algorithm exclusions that accurately predicts IBIs. This is the first study to derive an all-inclusive predictive model for febrile infants aged 7-60 days in a community ED sample with IBI as a primary outcome. This machine learning model demonstrates potential for clinical utility in predicting IBI.

Helical reconstruction of VP39 reveals principles for baculovirus nucleocapsid assembly.

Baculoviruses are insect-infecting pathogens with wide applications as biological pesticides, in vitro protein production vehicles and gene therapy tools. Its cylindrical nucleocapsid, which encapsulates and protects the circular double-stranded viral DNA encoding proteins for viral replication and entry, is formed by the highly conserved major capsid protein VP39. The mechanism for VP39 assembly remains unknown. We use electron cryomicroscopy to determine a 3.2 Å helical reconstruction of an infectious nucleocapsid of Autographa californica multiple nucleopolyhedrovirus, revealing how dimers of VP39 assemble into a 14-stranded helical tube. We show that VP39 comprises a distinct protein fold conserved across baculoviruses, which includes a Zinc finger domain and a stabilizing intra-dimer sling. Analysis of sample polymorphism shows that VP39 assembles in several closely-related helical geometries. This VP39 reconstruction reveals general principles for baculoviral nucleocapsid assembly.

Concurrent Sexually Transmitted Infections with Mpox Infections: A Brief Review.

Mpox is a viral zoonotic infection endemic to countries in Central and West Africa. The outbreak that began in May 2022 is novel for its global spread and transmission through sexual encounters. Research of this outbreak shows a high rate of concurrent sexually transmitted infections (STIs) in patients with mpox, highlighting the need to consider STIs in mpox management, and to raise awareness of historically high levels of STIs caused by inadequacies in sexual health care. It is critical to prioritize sexual health and address health disparities to control current transmission of infections and prevent future outbreaks.

Circulating tumor DNA and radiological tumor volume identify patients at risk for relapse with resected, early-stage non-small-cell lung cancer.

BACKGROUND: Predicting relapse and overall survival (OS) in early-stage non-small-cell lung cancer (NSCLC) patients remains challenging. Therefore, we hypothesized that detection of circulating tumor DNA (ctDNA) can identify patients with increased risk of relapse and that integrating radiological tumor volume measurement along with ctDNA detectability improves prediction of outcome. PATIENTS AND METHODS: We analyzed 366 serial plasma samples from 85 patients who underwent surgical resections and assessed ctDNA using a next-generation sequencing liquid biopsy assay, and measured tumor volume using a computed tomography-based three-dimensional annotation. RESULTS: Our results showed that patients with detectable ctDNA at baseline or after treatment and patients who did not clear ctDNA after treatment had a significantly worse clinical outcome. Integrating radiological analysis allowed the stratification in risk groups prognostic of clinical outcome as confirmed in an independent cohort of 32 patients. CONCLUSIONS: Our findings suggest ctDNA and radiological monitoring could be valuable tools for guiding follow-up care and treatment decisions for early-stage NSCLC patients.

Rate Versus Rhythm Control for Atrial Fibrillation.

Atrial fibrillation (AF) is an arrhythmia characterized by disorganized atrial activity with an associated unevenly irregular ventricular response on an electrocardiogram. It is the most common sustained arrhythmia, with a lifetime risk of 25% in patients older than 40 years old. The incidence of AF increases with age and is associated with an increased risk for heart failure, stroke, adverse cardiac events, and dementia. The 2 main aims of AF treatment include anticoagulation for thromboembolism prophylaxis as well as rate vs rhythm control. The focus of this article will be on the treatment strategies in managing AF. Rate control refers to the use of atrioventricular nodal blocking medications, including beta blockers and calcium channel blockers, to maintain a goal heart rate. Rhythm control, on the other hand, refers to a treatment strategy focused on the use of antiarrhythmic drugs (AAD), cardioversion, and ablation to restore and to maintain a patient in sinus rhythm. Currently, the ideal treatment strategy remains greatly debated. Thus, we hope to compare the risks and benefits of rate to rhythm control to highlight how patients with AF are managed here at Kaiser Permanente Northern California.

The role of legitimizing the social hierarchy in the impact of status on perceived assertiveness and competence.

The present research aimed to examine how perceivers' system-justifying beliefs moderate the way they evaluate high- versus low-status targets on assertiveness and competence. In three experimental studies, we manipulated a target's hierarchical position within his company's organization. Participants rated the target on traits reflecting assertiveness and competence. Their system-justifying beliefs were assessed in an ostensibly unrelated study. Results consistently showed that participants inferred assertiveness from the target's hierarchical position regardless of system justification, whereas the relationship between social status and competence was consistently moderated by system-justifying beliefs: only participants high in system justification ascribed more competence to the high-status target than to the low-status target. These findings are in line with the hypothesis suggesting that inferring competence from high-status positions could rely on the tendency to justify social inequalities, whereas inferring assertiveness would not.

Genetic and Functional Analyses of Cutibacterium Acnes Isolates Reveal the Association of a Linear Plasmid with Skin Inflammation.

Cutibacterium acnes is a commensal bacterium on the skin that is generally well-tolerated, but different strain types have been hypothesized to contribute to the disease acne vulgaris. To understand how some strain types might contribute to skin inflammation, we generated a repository of C. acnes isolates from skin swabs of healthy subjects and subjects with acne and assessed their strain-level identity and capacity to stimulate cytokine release. Phylotype II K-type strains were more frequent on healthy and nonlesional skin of subjects with acne than those isolated from lesions. Phylotype IA-1 C-type strains were increased on lesional skin compared with those on healthy skin. The capacity to induce cytokines from cultured monocyte-derived dendritic cells was opposite to this action on sebocytes and keratinocytes and did not correlate with the strain types associated with the disease. Whole-genome sequencing revealed a linear plasmid in high-inflammatory isolates within similar strain types that had different proinflammatory responses. Single-cell RNA sequencing of mouse skin after intradermal injection showed that strains containing this plasmid induced a higher inflammatory response in dermal fibroblasts. These findings revealed that C. acnes strain type is insufficient to predict inflammation and that carriage of a plasmid could contribute to disease.

Prominin 1 and Tweety Homology 1 both induce extracellular vesicle formation.

Prominin-1 (Prom1) is a five-transmembrane-pass integral membrane protein that associates with curved regions of the plasma membrane. Prom1 interacts with membrane cholesterol and actively remodels the plasma membrane. Membrane bending activity is particularly evident in photoreceptors, where Prom1 loss-of-function mutations cause failure of outer segment homeostasis, leading to cone-rod retinal dystrophy (CRRD). The Tweety Homology (Ttyh) protein family has been proposed to be homologous to Prominin, but it is not known whether Ttyh proteins have an analogous membrane-bending function. Here, we characterize the membrane-bending activity of human Prom1 and Ttyh1 in native bilayer membranes. We find that Prom1 and Ttyh1 both induce formation of extracellular vesicles (EVs) in cultured mammalian cells and that the EVs produced are biophysically similar. Ttyh1 is more abundant in EV membranes than Prom1 and produces EVs with membranes that are more tubulated than Prom1 EVs. We further show that Prom1 interacts more stably with membrane cholesterol than Ttyh1 and that this may contribute to membrane bending inhibition in Prom1 EVs. Intriguingly, a loss-of-function mutation in Prom1 associated with CRRD induces particularly stable cholesterol binding. These experiments provide mechanistic insight into Prominin function in CRRD and suggest that Prom and Ttyh belong to a single family of functionally related membrane-bending, EV-generating proteins.

Enhancing classical swine fever virus identification: the advantages of Field-LAMP testing.

Classical swine fever virus (CSFV) identification has witnessed significant advancements with the development of rapid reverse-transcription loop-mediated isothermal amplification (RT-LAMP) assays. However, conventional RT-LAMP assays for CSFV diagnosis are hindered by a laborious RNA extraction step. Moreover, the need for thermal incubators and expensive micropipettes has limited their application in field settings. Addressing these challenges, our study presents a groundbreaking solution-an electro-free and point-of-care (POC) tool known as the field-LAMP assay-for the rapid clinical detection of CSFV. By eliminating the RNA extraction requirement, advancing the colorimetric read-out and lyophilized reaction reagents, our field-LAMP assay streamlines the diagnostic process, saving valuable time and effort. This novel approach also overcomes the dependency on electric-dependent thermal incubators and expensive micropipettes, making it practical and accessible for use in the field. The successful development of the field-LAMP assay marks a significant milestone in CSFV detection. This electro-free and POC tool offers several advantages, including its ability to deliver rapid results without compromising accuracy, facilitating prompt response and containment measures.

Beneficial effects of pulmonary embolism response team establishment in patients with pulmonary embolism in a developing country: a single-center experience.

Objective: The impact of establishing a pulmonary embolism response team (PERT) in patients with pulmonary embolism (PE) has been proven in many developed countries. However, the efficacy of a PERT largely depends on expertise and infrastructure. This study explored the benefit of establishing a PERT in developing countries with limited healthcare resources by comparing the outcomes of patients with acute PE before and after PERT establishment at University Medical Center Ho Chi Minh City in Vietnam. Methods: We conducted a single-center observational study from January 1, 2019, to August 1, 2021. All patients with PE confirmed on computed tomography were included. Patients admitted before PERT establishment were treated by cardiologists alone, while those hospitalized after PERT establishment were managed by the PERT. Results: A total of 130 patients were included (pre-PERT estab-lishment: 51 patients; post-PERT establishment: 79 patients). The demographic characteristics, severity of PE, and clinical and laboratory findings were similar between the two groups. The post-PERT establishment group had a lower incidence rate of major and clinically relevant nonmajor bleeding (11.3% vs. 31.4%, p = 0.005) and required more interventional therapies (16.5% vs. 3.9%, p = 0.046) than did the pre-PERT establishment group. The in-hospital mortality rate decreased in the post-PERT establishment group compared with that in the pre-PERT establishment group (8.9% vs. 21.6%, p = 0.041). Conclusions: Involvement of the PERT in PE management was associated with improved outcomes of patients with PE, including reduced bleeding and mortality rates in a resource-constrained hospital.

Electric Fields in Liquid Water Irradiated with Protons at Ultrahigh Dose Rates.

We study the effects of irradiating water with 3 MeV protons at high doses by observing the motion of charged polystyrene beads outside the proton beam. By single-particle tracking, we measure a radial velocity of the order of microns per second. Combining electrokinetic theory with simulations of the beam-generated reaction products and their outward diffusion, we find that the bead motion is due to electrophoresis in the electric field induced by the mobility contrast of cations and anions. This work sheds light on the perturbation of biological systems by high-dose radiations and paves the way for the manipulation of colloid or macromolecular dispersions by radiation-induced diffusiophoresis.

Clinical evaluation of hysterectomy for the treatment of invasive mole in Southern Vietnam.

OBJECTIVE: This study aimed to determine the rate of salvage chemotherapy and review associated factors in invasive mole patients treated by primary or delayed hysterectomy. PATIENTS AND METHODS: This study was carried out at the Tu Du Hospital, where a total of 189 patients were diagnosed with invasive mole based on histologic examination by hysterectomy between 01/2016 to 12/2020. We used the life table method to estimate the cumulative rate. We applied the Cox proportional hazard model to determine the factors associated with the need for salvage chemotherapy. RESULTS: At 12-month follow-up, 47 patients had required salvage chemotherapy. The incidence was 24.87% (95% CI: 18.88-31.66). Applying the multivariate model, prophylactic chemotherapy (HR = 2.75, 95% Cl: 1.20-6.30) and two weeks postoperative hCG value greater than 1,900 mIU/mL (HR = 4.30, 95% Cl: 2.08-8.87) increased the risk of requiring salvage chemotherapy. Postoperative chemotherapy decreased the risk of requiring salvage chemotherapy (HR = 0.43, 95% Cl: 0.22-0.83). CONCLUSIONS: Hysterectomy can be considered safe and effective in treating invasive mole patients. Although patients were treated by hysterectomy, 24.87% of patients needed salvage chemotherapy to achieve remission. This study affirms the malignant nature of invasive mole, a subtype of gestational trophoblastic neoplasia (GTN). It is not purely a local invasion of molar villi. Postoperative chemotherapy plays an essential role in reducing the risk of requiring salvage chemotherapy.

Calculation of electron interaction models in N2 and O2.

Cosmic rays have the potential to significantly affect the atmospheric composition by increasing the rate and changing the types of chemical reactions through ion production. The amount and states of ionization, and the spatial distribution of ions produced are still open questions for atmospheric models. To precisely estimate these quantities, it is necessary to simulate particle-molecule interactions, down to very low energies. Models enabling such simulations require interaction probabilities over a broad energy range and for all energetically allowed scattering processes. In this paper, we focus on electron interaction with the two most abundant molecules in the atmosphere, i.e., N2 and O2, as an initial step. A set of elastic and inelastic cross section models for electron transportation in oxygen and nitrogen molecules valid in the energy range 10 eV - 1 MeV, is presented. Comparison is made with available theoretical and experimental data and a reasonable good agreement is observed. Stopping power is calculated and compared with published data to assess the general consistency and reliability of our results. Good overall agreement is observed, with relative differences lower than 6% with the ESTAR database.

Financial toxicity among cancer patients, survivors and their families in the United Kingdom: a scoping review.

BACKGROUND: The aim of this scoping review was to identify key research gaps and priorities in order to advance policy and practice for people living with cancer in the UK. METHODS: The review adhered to PRISMA guidelines for scoping review. We searched MEDLINE, EMBASE, Scopus, Web of Science and Google Scholar on 16 July 2022. There were no restrictions in terms of study design and publication time; gray literature was included. The key words, 'financial' or 'economic', were combined with each of the following words 'hardship/stress/burden/distress/strain/toxicity/catastrophe/consequence/impact.' RESULTS: 29/629 studies/reports published during 1982-2022 were eligible to be included in the review. No study conducted a comprehensive inquiry and reported all aspects of financial toxicity (FT) or used a validated measure of FT. The most three commonly reported outcomes related to financial hardship were financial well-being (24/29), benefit/welfare (17/29) and mental health status (16/29). CONCLUSIONS: It is evident that FT is experienced by UK cancer patients/survivors and that the issue is under-researched. There is an urgent need for further research including rigorous studies which contribute to a comprehensive understanding about the nature and extent of FT, disparities in experience, the impacts of FT on outcomes and potential solutions to alleviate FT and related problems.

Helical reconstruction of VP39 reveals principles for baculovirus nucleocapsid assembly.

Baculoviruses are insect-infecting pathogens with wide applications as biological pesticides, in vitro protein production vehicles and gene therapy tools. Its cylindrical nucleocapsid, which encapsulates and protects the circular double-stranded viral DNA encoding proteins for viral replication and entry, is formed by the highly conserved major capsid protein VP39. The mechanism for VP39 assembly remains unknown. We determined a 3.2 Å electron cryomicroscopy helical reconstruction of an infectious nucleocapsid of Autographa californica multiple nucleopolyhedrovirus, revealing how dimers of VP39 assemble into a 14-stranded helical tube. We show that VP39 comprises a unique protein fold conserved across baculoviruses, which includes a Zinc finger domain and a stabilizing intra-dimer sling. Analysis of sample polymorphism revealed that VP39 assembles in several closely-related helical geometries. This VP39 reconstruction reveals general principles for baculoviral nucleocapsid assembly.

Intensity- and frequency-specific effects of transcranial alternating current stimulation are explained by network dynamics.

Transcranial alternating current stimulation (tACS) can be used to non-invasively entrain neural activity, and thereby cause changes in local neural oscillatory power. Despite an increased use in cognitive and clinical neuroscience, the fundamental mechanisms of tACS are still not fully understood. Here, we develop a computational neuronal network model of two-compartment pyramidal neurons and inhibitory interneurons which mimic the local cortical circuits. We model tACS with electric field strengths that are achievable in human applications. We then simulate intrinsic network activity and measure neural entrainment to investigate how tACS modulates ongoing endogenous oscillations. First, we show that intensity-specific effects of tACS are non-linear. At low intensities (<0.3 mV/mm), tACS desynchronizes neural firing relative to the endogenous oscillations. At higher intensities (>0.3 mV/mm), neurons are entrained to the exogenous electric field. We then further explore the stimulation parameter space and find that entrainment of ongoing cortical oscillations also depends on frequency by following an Arnold tongue. Moreover, neuronal networks can amplify the tACS induced entrainment via excitation-inhibition balance. Our model shows that pyramidal neurons are directly entrained by the exogenous electric field and drive the inhibitory neurons. Our findings can thus provide a mechanistic framework for understanding the intensity- and frequency- specific effects of oscillating electric fields on neuronal networks. This is crucial for rational parameters selection for tACS in cognitive studies and clinical applications.

Uncovering hypercoagulation status using rotational thromboelastometry in patients with sepsis presented with hypocoagulation based on conventional coagulation tests: an observational study.

OBJECTIVE: Conventional coagulation tests (CCTs) cannot identify hypercoagulation, despite being common in patients with sepsis. Moreover, CCTs overdiagnose hypocoagulation, which increases unnecessary blood transfusion. Therefore, we aimed to use rotational thromboelastometry (ROTEM) to classify the coagulation status of patients with sepsis with abnormal CCTs and to identify the main coagulation components that affect coagulation status. PATIENTS AND METHODS: This study was part of an observational study to investigate ROTEM use in 161 patients with sepsis with the Sepsis-3 criteria. They underwent concurrent CCTs and ROTEM assessments within 24 hours of Intensive Care Unit admission at the University Medical Center, Ho Chi Minh City, from June 2020 to December 2021. This study only extracted data from patients with sepsis with abnormal CCTs, including activated partial thromboplastin time ratio, international normalized ratio (INR), platelet count, and fibrinogen concentration. RESULTS: A total of 158 patients with sepsis with abnormal CCTs had a median age of 69, and 48.7% were women. Of 34 patients with INR ≥1.6, ROTEM identified 11.8% with hypercoagulation and 20.6% with normal coagulation. Of 29 patients with platelet counts <100 (103/mm3), ROTEM identified 3.5% with hypercoagulation and 24.1% with normal coagulation. In the ROTEM-based hypercoagulability group, an increase in maximum clot firmness was observed in 95.1% of cases; also, this group had significantly higher plasma fibrinogen concentrations than other groups (p<0.005). CONCLUSIONS: ROTEM can reveal hypercoagulability in patients with sepsis with hypocoagulation based on CCTs. Hyperfibrinogenemia causes hypercoagulation in patients with sepsis.