bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of turoctocog alfa in patients with hemophilia A requiring surgical procedures: A multicentre retrospective study
Authors: Drillaud Nicolas , Cussac Vincent , Bertho Pierre‐Olivier , Horvais Valérie , Beurrier Philippe , Ternisien Catherine , Rose Johann , Fouassier Marc , Babuty Antoine , Trossaërt Marc
Published: October 2023

Background

Turoctocog alfa is a recombinant Factor VIII used in patients with hemophilia A. The aim is to assess the real‐life evidence of turoctocog alfa in surgery.

Study Design and Methods

Data were extracted from a national database.

Results

Turoctocog alfa was used for 86 surgeries (49 major and 37 minor) in 56 patients. The results are expressed as medians (interquartile range).

Six (10.7%) patients had severe hemophilia A, four (7.1%) moderate, and 46 (82.2%) mild. For patients who underwent major surgeries, basal plasma FVIII coagulant activity (FVIII:C) levels were 15 IU.dL−1 (8–22). Eight (5–14) infusions were given, at a preoperative loading dose of 40.0 (35.0–45.5) IU.kg−1 and a total dose of 253.3 (125.0–507.0) IU.kg−1. In patients who underwent minor surgeries, basal FVIII:C levels were 18 IU.dL−1 (9–31). Two (1–3) infusions were required, at a preoperative loading dose of 34.0 (28.8–38.5) IU.kg−1 and a total dose of 73.7 (37.6–122.1) IU.kg−1. The overall clinical efficacy was judged excellent/good in 77 procedures (89.5%) and fair/poor in nine (10.5%). The fair/poor efficacy concerned seven patients (six mild hemophilia and one severe), for four urological surgeries, two dermatological procedures, one heart surgery, one ear‐nose‐throat procedure, and one dental avulsion in the patient with severe hemophilia. Three out of those seven patients received antiplatelet therapy. No thromboembolic events, anti‐FVIII antibodies, or adverse events were reported.

Discussion

The efficacy and safety of turoctocog alfa were confirmed for the management of surgery in patients with hemophilia A. No adverse events were observed and overall efficacy was good.
Regulatory convergence within technical barriers to trade
Authors: Ghodsi Mahdi
Published: October 2023

This paper analyses how regulatory convergence in different categories of technical barriers to trade (TBTs) imposed on imports of goods in information and communications technology (ICT) globally affected the values, volumes and unit values of imported goods during the period 1996–2019. Keywords cited in TBTs that are notified to the World Trade Organisation (WTO) give an indication of the regulatory objectives behind the imposition of TBTs. MAST also classifies TBTs based on their applicability, procedural and administrative uses, factors which will also be taken into consideration in the analysis. However, the objectives of TBTs may provide better insights to policymakers. TBTs are non‐discriminatory measures that are imposed unilaterally on all trading partners and on domestic producers. It is not feasible to analyse unilateral TBTs in a gravity setting, as they are excluded by the introduction of country‐product‐time fixed effects that control for multilateral resistances. However, regulatory convergence in TBT categories is a bilateral time‐varying variable that is analysed in a gravity model in this paper. The empirical results suggest that regulatory convergence between trading partners in some TBT categories stimulates import values and volumes. However, the impact is very heterogeneous across TBT objectives and classes and across ICT product categories.
Presumed residual thymic tissue is a common finding in thoracic computed tomography in adult dogs
Authors: Vester Siemone C. , Bergmann Wilhelmina , van den Broek Dirk H. N. , Veraa Stefanie , Schaafsma Irene A.
Published: October 2023

Residual thymic tissue is a common incidental finding in thoracic CT of human adults. To determine whether presumed residual thymic tissue is also a common incidental finding in adult dogs, a two part‐study was performed. The first part was a prospective, descriptive design where CT examination was performed in six canine cadavers within 24 h after death and presumed residual thymic tissue was examined pathologically. The second part of the study was a retrospective, analytical design where medical records of our institution were searched for thoracic CT scans of adult dogs performed in the year 2020. Age, sex, breed, presence of presumed thymic tissue, location, shape, attenuation, homogeneity, and width of the tissue were recorded and comparisons were performed using these data. In 4 of 6 of the prospective cases, thymic tissue was present on histology and in 2 of 6 dogs the presence of thymic tissue could not be confirmed. For the retrospective study, in 161/169 (95.3%) cases with presumed residual thymic tissue were detected. Shape and size were highly variable with either homogeneous (46.6%), heterogeneous (42.9%), or mixed (10.6%) attenuation. Dogs with presumed residual thymic tissue were significantly younger (median: 9.1 years; range: 1.2–14.3 vs. median: 10.5 years; range: 9.4–12.3) as were dogs with homogeneous attenuation of the tissue (median: 8.1 years; range: 1.2–14.3 vs. median: 9.5 years; range: 4.0–14.3). In conclusion, results indicated that presumed residual thymic tissue is a common CT finding in adult dogs and can be considered incidental.
Totally real algebraic integers in short intervals, Jacobi polynomials, and unicritical families in arithmetic dynamics
Authors: Noytaptim Chatchai , Petsche Clayton
Published: October 2023

We classify all postcritically finite unicritical polynomials defined over the maximal totally real algebraic extension of . Two auxiliary results used in the proof of this result may be of some independent interest. The first is a recursion formula for the diameter of an interval, which uses properties of Jacobi polynomials. The second is a numerical criterion that allows one to give a bound on the degree of any algebraic integer having all of its complex embeddings in a real interval of length less than 4.
Leveraging Additive Manufacturing to Fabricate High Temperature Alloys With Co-Designed Mechanical Properties and Environmental Resistance
Authors: Pillai R. , Ren Q.Q. , Su Yi-Feng , Kurfess Rebecca , Feldhausen Thomas , Nag Soumya
Published: October 2023

A paradigm shift in the traditional sequential design approaches is critically essential to create application-specific hierarchical and multifunctional materials with superior long-term performance for next-generation energy technologies involving extreme environments. In the current work, we aim to leverage the flexibility and geometric/compositional complexity offered by additive manufacturing to demonstrate this new approach by codesigning a compositionally graded Ni-based alloy for molten salts\sCO2 heat exchangers to enable mitigation of environmental degradation of surfaces exposed to molten halide salts, while simultaneously suppressing the consequent deterioration in mechanical stability. Thermokinetic modeling describing the underlying physics of thermally- and environmentally induced spatiotemporal compositional and microstructural evolution will be employed to predict the parameter space of material deposition processes and precisely identify the required composition gradient. Preliminary corrosion and mechanical testing of the dual material demonstrated the potential of the material to replace existing solid solution strengthened materials for this application.
Performance, Emissions, and Decarbonization of an Industrial Gas Turbine Operated With Hydrotreated Vegetable Oil
Authors: Runyon Jon , James Stuart , Kadam Tanmay , Ofir Barak , Graham David
Published: October 2023

As part of Uniper's strategy for carbon neutrality in its European power generation by 2035, a Kraftwerk Union/Siemens V93.0 gas turbine (GT) in Malmö, Sweden was operated with hydrotreated vegetable oil (HVO) as a low-carbon replacement for gas oil in July 2021. Prior to HVO operation, a feasibility study was conducted including fuel comparison, flame temperature modeling, and a hazard identification study. During the two-day demonstration, GT performance was monitored using either gas oil or HVO at startup, full load, part load, and shut-down. Accredited emissions of NOx, CO, SO2, and dust were measured to allow comparison between fuels. When firing HVO, no adverse GT operations were encountered, and direct flame imaging was used to observe the successful HVO ignition process at startup. NOx emissions were nominally similar to gas oil during HVO operation. Therefore, the water injection rate for NOx control was unchanged between fuels, confirming the predictions of the flame temperature modeling. Dust, CO, and SO2 emissions reduced during HVO operation. HVO also enables significant lifecycle CO2 emissions reductions compared with fossil gas oil with ∼163 tCO2 emissions avoided in this trial. This trial provides evidence for future site fuel conversion. Further testing and monitoring is required to develop evidence regarding the long-term impact of HVO operation on fuel storage, fuel delivery, and hot gas path components. To the authors' knowledge, this trial is the first successful demonstration of HVO use in an industrial gas turbine in the world.
Spatially Resolved Modeling of the Nonlinear Dynamics of a Laminar Premixed Flame With a Multilayer Perceptron—Convolution Autoencoder Network
Authors: Rywik Marcin , Zimmermann Axel , Eder Alexander J. , Scoletta Edoardo , Polifke Wolfgang
Published: October 2023

This work presents a multilayer perceptron-convolutional auto-encoder (MLP-CAE) neural network, which accurately predicts the two-dimensional flame dynamics of an acoustically excited premixed laminar flame. The architecture maps the acoustic perturbation time series into a heat release rate field, capturing flame lengths and shapes. This extends previous neural network models, which predicted only the field-integrated value. The MLP-CAE comprises two submodels: an MLP and a CAE. The idea behind the CAE network is to find a lower dimensional latent space of the heat release rate field. The MLP is responsible for modeling the flame dynamics by transforming the acoustic forcing signal into this latent space, enabling the decoder to produce the flow field distributions. To train the MLP-CAE, computational fluid dynamics (CFD) flame simulations with a broadband acoustic forcing were used. Its normalized amplitude was set to 0.5 and 1.0, ensuring a nonlinear flame response. The network was found to accurately predict the perturbed flame shapes. Additionally, it conserved the correct frequency response as verified by the global and local flame describing functions. The MLP-CAE provides a building block toward a potential shift away from a “0D” flame analysis with the acoustic compactness assumption. Combined with an acoustic network, the generated flame fields could provide more physical insight into the thermoacoustic dynamics. Those capabilities do not come at an additional significant computational cost, as even previous nonspatial flame models had to train on the CFD data, which included field distributions.
A Fault Detection Framework Based on Data-Driven Digital Shadows
Authors: Michalski Miguel Angelo de Carvalho , Melani Arthur Henrique de Andrade , da Silva Renan Favarão , de Souza Gilberto Francisco Martha
Published: October 2023

The popularization of Industry 4.0 and its technological pillars has allowed prognostics and health management (PHM) strategies to be applied in complex systems to optimize their performance and extend their useful life by taking advantage of a digitalized, integrated environment. Due to this context, the use of digital twins and digital shadows, which are virtual representations of physical systems that provide real-time monitoring and analysis of the health and performance of the system, has been increasingly used in the application of fault detection, a key component of PHM. Taking that into consideration, this work proposes a framework for fault detection in engineering systems based on the construction and application of a digital shadow. This digital shadow is based on a digital model composed of a system of equations and a continuous, real-time communication process with a supervisory control and data acquisition (SCADA) system. The digital model is generated using monitoring data from the system under study. The proposed method was applied in two case studies, one based on synthetic data and another that uses a simulated database of an operational generating unit of a hydro-electric power plant. The method, in both case studies, was able to detect faults accurately and effectively. Besides, the method provides by-products that can be used in the future in other applications, helping with the PHM in other aspects.
Incorporating Diversity, Equity, and Inclusion Content Into Bioengineering Curricula: A Program-Level Approach
Authors: Mollica Molly Y. , Olszewski Emily , Kiyohara Casey L. , Matusalem Danafe D. , Ochs Alexander R. , Imoukhuede Princess I. , Regnier Michael , Yasuhara Ken , Thomas Wendy E. , Taylor Alyssa C.
Published: October 2023

Diversity, equity, and inclusion (DEI) are interconnected with bioengineering, yet have historically been absent from accreditation standards and curricula. Toward educating DEI-competent bioengineers and meeting evolving accreditation requirements, we took a program-level approach to incorporate, catalog, and assess DEI content through the bioengineering undergraduate program. To support instructors in adding DEI content and inclusive pedagogy, our team developed a DEI planning worksheet and surveyed instructors pre- and post-course. Over the academic year, 74% of instructors provided a pre-term and/or post-term response. Of responding instructors, 91% described at least one DEI curricular content improvement, and 88% incorporated at least one new inclusive pedagogical approach. Based on the curricular adjustments reported by instructors, we grouped the bioengineering-related DEI content into five DEI competency categories: bioethics, inclusive design, inclusive scholarship, inclusive professionalism, and systemic inequality. To assess the DEI content incorporation, we employed direct assessment via course assignments, end-of-module student surveys, end-of-term course evaluations, and an end-of-year program review. When asked how much their experience in the program helped them develop specific DEI competencies, students reported a relatively high average of 3.79 (scale of 1 = “not at all” to 5 = “very much”). Additionally, based on student performance in course assignments and other student feedback, we found that instructors were able to effectively incorporate DEI content into a wide variety of courses. We offer this framework and lessons learned to be adopted by programs similarly motivated to train DEI-competent engineering professionals and provide an equitable, inclusive engineering education for all students.
Biomechanical Evaluation of Tracheal Needle Puncture Forces: Comparative Analysis of Annular Ligaments and Tracheal Cartilage
Authors: Sissoko Cheick , Walker Victoria , Dion Gregory R.
Published: October 2023

Percutaneous tracheotomies (PCT) are commonly performed minimally invasive procedures involving the creation of an airway opening through an incision or puncture of the tracheal wall. While the medical intervention is crucial for critical care and the management of acute respiratory failure, tracheostomy complications can lead to severe clinical symptoms due to the alterations of the airways biomechanical properties/structures. The causes and mechanisms underlaying the development of these post-tracheotomy complications remain largely unknown. In this study, we aimed to investigate the needle puncture process and its biomechanical characteristics by using a well establish porcine ex vivo trachea to simulate the forces involved in accessing airways during PCT at varying angular approaches. Given that many procedures involve inserting a needle into the trachea without direct visualization of the tracheal wall, concerns have been raised over the needle punctures through the cartilaginous rings as compared to the space between them may result in fractured cartilage and post-tracheostomy airway complications. We report a difference in puncture force between piercing the cartilage and the annular ligaments and observe that the angle of puncture does not significantly alter the puncture forces. The data collected in this study can guide the design of relevant biomechanical feedback system during airway access procedures and ultimately help refine and optimize PCT.
An Approach to Quantify Anisotropic Multiaxial Failure of the Annulus Fibrosus
Authors: Middendorf Jill M. , Barocas Victor H.
Published: October 2023

Tears in the annulus fibrosus (AF) of the intervertebral disk (IVD) occur due to multiaxial loading on the spine. However, most existing AF failure studies measure uniaxial stress, not the multiaxial stress at failure. Delamination theory, which requires advanced structural knowledge and knowledge about the interactions between the AF fibers and matrix, has historically been used to understand and predict AF failure. Alternatively, a simple method, the Tsai-Hill yield criteria, could describe multiaxial failure of the AF. This yield criteria uses the known tissue fiber orientation and an equation to establish the multiaxial failure stresses that cause failure. This paper presents a method to test the multiaxial failure stress of the AF experimentally and evaluate the potential for the Tsai-Hill model to predict these failure stresses. Porcine AF was cut into a dogbone shape at three distinct angles relative to the primary lamella direction (parallel, transverse, and oblique). Then, each dogbone was pulled to complete rupture. The Cauchy stress in the material's fiber coordinates was calculated. These multiaxial stress parameters were used to optimize the coefficients of the Tsai-Hill yield. The coefficients obtained for the Tsai-Hill model vary by an order of magnitude between the fiber and transverse directions, and these coefficients provide a good description of the AF multiaxial failure stress. These results establish both an experimental approach and the use of the Tsai-Hill model to explain the anisotropic failure behavior of the tissue.
Effects of Product Personalization: Considering Personalizability in the Product Architecture of Modular Product Families
Authors: Vogt Juliane , Woeller Lea-Nadine , Krause Dieter
Published: October 2023

The modularity of a product architecture with standard, variant, and optional modules can be measured by the characteristics of commonality and combinability. Positive and negative effects of a more communal or more combinable structure are summarized and visualized in an impact model. However, due to the megatrend of personalization, the solution space of a modular product architecture needs to be extended to include personalizable modules. What remains unclear till now is how personalization impacts the different life phases. Therefore, this article derives an impact model considering product personalization. First, the modularity property of personalizability is derived, in order to then specifically investigate the effects occurring in the different life phases. Therefore, a literature review is conducted. New effects are found, and the existing effects of commonality and combinability are examined for their validity for personalizability. The findings are then combined with the known effects of commonality and combinability to create a holistic impact model of modular product families. This new model takes personalizable modules into account and can support companies in defining the goals and focus of a modularization project.
Effect of Outlet Shape on Flame Height of Transformer Oil Jet Fire Under External Fire Source
Authors: Sun Shaodong , Chen Peng , Zhai Xu , Liu Yang
Published: October 2023

In this inquiry, we delve into the manner by which disparate orifice configurations exert influence upon the elevation of the jet flame when subjected to an external conflagration, employing empirical simulations. Elaborating upon the empirical dataset, we introduce the derivative of hydraulic diameter alterations and the velocity of material degradation, thereby revising the traditional non-dimensionalized model of flame altitude. The revelations disclose that, across an array of orifice profiles, the conflagration jet within oil-laden apparatus undergoes four discernible phases of evolution, each replete with variable flambeau altitudes. In disparate operational circumstances, the quantified velocity of material degradation during the evolution phase manifests an exponential interrelation with the approximated value of the model. Conversely, the phases of stability and decline adhere to a potency function connection. A quantitative delineation of the pivotal states for each phase of combustion is achieved through the evaluation of the rate of alteration in the velocity of material degradation. Significantly, the pivotal juncture for the proliferation and equilibrium stage is ascertained to be 2 g/s. This scientific inquiry confers invaluable theoretical reinforcement for fire safeguarding and catastrophe evaluation within substations accommodating oil-infused apparatus.
Effects of a Self-Pressurized Injection Strategy on the Formation of a Stratified Mixture and the Combustion of an Aviation Kerosene Piston Engine
Authors: Ji Haocheng , Zhong Lingfeng , Li Songhong , Chen Yufeng , Liu Rui
Published: October 2023

The aviation kerosene piston engine (AKPE) is the main power system for small- and medium-sized unmanned aerial vehicles (UAVs). Conventional AKPEs use carburetors or port fuel injection (PFI) as fuel supply, resulting in poor cold start performance and difficulty in forming an economically efficient stratified mixture. In addition, two-stroke AKPEs using carburetors or PFI have serious scavenging losses. These reasons lead to the poor economic performance of conventional AKPEs. Direct injection (DI) can be controlled through precise injection timing to form a stratified mixture. The combustion of stratified mixtures in engines can effectively improve the fuel economy and endurance flight time characteristics of UAVs. As a special DI injector, self-pressurized injectors have great potential in the power field of UAVs. To effectively apply self-pressurized injectors on UAV engines and improve the economy, an engine model and a self-pressurized injector spray model are established and verified in this paper. The single injection strategy and segmented injection strategy for forming stratified mixtures are explored, and the combustion performance is studied. The main conclusions are as follows: the optimal installation angle of the injector is 15 deg, which yields excellent results in the formation of the mixture at this angle. When the fuel injection quantity is small, utilizing a single injection strategy combined with delaying the end of the injection phase (EOIP) can form a stratified mixture. Reducing the angle difference between the EOIP and the ignition timing can improve the power and economy. As the fuel injection quantity is large, a stratified mixture can be formed through two-stage injection. When the fuel injection ratio is 4:1, the uniformity of the mixture distribution in the combustion chamber is significantly improved. Adjusting the second EOIP between a 35 deg crank angle (CA) before top dead center (BTDC) and a 30 deg CA BTDC can achieve a stratified mixture with good economy and power performance.
Ultrasound imaging of lung disease and its relationship to histopathology: An experimentally validated simulation approach
Authors: Ostras Oleksii , Shponka Ihor , Pinton Gianmarco
Published: October 2023

Lung ultrasound (LUS) is a widely used technique in clinical lung assessment, yet the relationship between LUS images and the underlying disease remains poorly understood due in part to the complexity of the wave propagation physics in complex tissue/air structures. Establishing a clear link between visual patterns in ultrasound images and underlying lung anatomy could improve the diagnostic accuracy and clinical deployment of LUS. Reverberation that occurs at the lung interface is complex, resulting in images that require interpretation of the artifacts deep in the lungs. These images are not accurate spatial representations of the anatomy due to the almost total reflectivity and high impedance mismatch between aerated lung and chest wall. Here, we develop an approach based on the first principles of wave propagation physics in highly realistic maps of the human chest wall and lung to unveil a relationship between lung disease, tissue structure, and its resulting effects on ultrasound images. It is shown that Fullwave numerical simulations of ultrasound propagation and histology-derived acoustical maps model the multiple scattering physics at the lung interface and reproduce LUS B-mode images that are comparable to clinical images. However, unlike clinical imaging, the underlying tissue structure model is known and controllable. The amount of fluid and connective tissue components in the lung were gradually modified to model disease progression, and the resulting changes in B-mode images and non-imaging reverberation measures were analyzed to explain the relationship between pathological modifications of lung tissue and observed LUS.
Passive ranging of a moving target in the direct-arrival zone in deep sea using a single vector hydrophone
Authors: Zhang Qi , Da Lianglong , Wang Chao , Yuan Meng , Zhang Yanhou , Zhuo Jianghao
Published: October 2023

The vector hydrophone covers more comprehensive sound field information over the sound pressure hydrophone. The passive target ranging method based on the shallow-located unmanned platform equipped with vector hydrophones is explored based on the measured surface ship data acquired in the deep-sea area in December 2021. First, a bearings-only target motion analysis (TMA) algorithm is proposed, determining the motion state of a moving target (e.g., azimuth angle, abeam time, heading angle, and the ratio of velocity to initial distance) in accordance with its horizontal bearing time recording (BTR) data. Subsequently, the loss function is built following the situation information and the average complex acoustic intensity to determine the real-time grazing angle of the target. Last, the real-time range of the target is determined in accordance with the situation information and the grazing angle. As revealed by the comparison of the calculated value of the sea trial data with the GPS trajectory, the average distance error of the target reaches 11.6%, the root mean square error (RMSE) of the grazing angle is 1.99°, the RMSE of the velocity is 1.9 kn, and the RMSE of the abeam time reaches 51.4 s.
Sex-dependent fear memory impairment in cocaine-sired rat offspring
Authors: Rich Matthew T. , Worobey Samantha J. , Mankame Sharvari , Pang Zhiping P. , Swinford-Jackson Sarah E. , Pierce R. Christopher
Published: October 2023

Cocaine self-administration by male rats results in neuronal and behavioral alterations in offspring, including responses to cocaine. Given the high degree of overlap between the brain systems underlying the pathological responses to cocaine and stress, we examined whether sire cocaine taking would influence fear-associated behavioral effects in drug-naïve adult male and female progeny. Sire cocaine exposure had no effect on contextual fear conditioning or its extinction in either male or female offspring. During cued fear conditioning, freezing behavior was enhanced in female, but not male, cocaine-sired progeny. In contrast, male cocaine-sired progeny exhibited enhanced expression of cue-conditioned fear during extinction. Long-term potentiation (LTP) was robust in the basolateral amygdala (BLA), which encodes fear conditioning, of female offspring but was completely absent in male offspring of cocaine-exposed sires. Collectively, these results indicate that cued fear memory is enhanced in the male progeny of cocaine exposed sires, which also have BLA synaptic plasticity deficits.
A multiscale generative model to understand disorder in domain boundaries
Authors: Dan Jiadong , Waqar Moaz , Erofeev Ivan , Yao Kui , Wang John , Pennycook Stephen J. , Loh N. Duane
Published: October 2023

A continuing challenge in atomic resolution microscopy is to identify significant structural motifs and their assembly rules in synthesized materials with limited observations. Here, we propose and validate a simple and effective hybrid generative model capable of predicting unseen domain boundaries in a potassium sodium niobate thin film from only a small number of observations, without expensive first-principles calculations or atomistic simulations of domain growth. Our results demonstrate that complicated domain boundary structures spanning 1 to 100 nanometers can arise from simple interpretable local rules played out probabilistically. We also found previously unobserved, significant, tileable boundary motifs that may affect the piezoelectric response of the material system, and evidence that our system creates domain boundaries with the highest configurational entropy. More broadly, our work shows that simple yet interpretable machine learning models could pave the way to describe and understand the nature and origin of disorder in complex materials, therefore improving functional materials design.
Multiomic profiling of cutaneous leishmaniasis infections reveals microbiota-driven mechanisms underlying disease severity
Authors: Farias Amorim Camila , Lovins Victoria M. , Singh Tej Pratap , Novais Fernanda O. , Harris Jordan C. , Lago Alexsandro S. , Carvalho Lucas P. , Carvalho Edgar M. , Beiting Daniel P. , Scott Phillip , Grice Elizabeth A.
Published: October 2023

Leishmania braziliensis
is a parasitic infection that can result in inflammation and skin injury with highly variable and unpredictable clinical outcomes. Here, we investigated the potential impact of microbiota on infection-induced inflammatory responses and disease resolution by conducting an integrated analysis of the skin microbiome and host transcriptome on a cohort of 62 patients infected with
L. braziliensis
. We found that overall bacterial burden and microbiome configurations dominated with
Staphylococcus
spp. were associated with delayed healing and enhanced inflammatory responses, especially by IL-1 family members. Quantification of host and bacterial transcripts on human lesions revealed that high lesional
S. aureus
transcript abundance was associated with delayed healing and increased expression of IL-1β. This cytokine was critical for modulating disease outcomes in
L. braziliensis
–infected mice colonized with
S. aureus
, given that its neutralization reduced pathology and inflammation. These results highlight how the human microbiome can shape disease outcomes in cutaneous leishmaniasis and suggest pathways toward host-directed therapies to mitigate the inflammatory consequences.
Dolutegravir pharmacokinetics in Ugandan patients with TB and HIV receiving standard- versus high-dose rifampicin
Authors: Kengo Allan , Nabisere Ruth , Gausi Kamunkhwala , Musaazi Joseph , Buzibye Allan , Omali Denis , Aarnoutse Rob , Lamorde Mohammed , Dooley Kelly E. , Sloan Derek James , Denti Paolo , Sekaggya-Wiltshire Christine
Published: October 2023

Higher rifampicin doses may improve tuberculosis treatment outcomes. This could however exacerbate the existing drug interaction with dolutegravir. Moreover, the metabolism of dolutegravir may also be affected by polymorphism of
UGT1A1,
a gene that codes for uridine diphosphate glucuronosyltransferase. We used population pharmacokinetic modeling to compare the pharmacokinetics of dolutegravir when coadministered with standard- versus high-dose rifampicin in adults with tuberculosis and HIV, and investigated the effect of genetic polymorphisms. Data from the SAEFRIF trial, where participants were randomized to receive first-line tuberculosis treatment with either standard- 10 mg/kg or high-dose 35 mg/kg rifampicin alongside antiretroviral therapy, were used. The dolutegravir model was developed with 211 plasma concentrations from 44 participants. The median (interquartile range) rifampicin area under the curve (AUC) in the standard- and high-dose arms were 32.3 (28.7–36.7) and 153 (138−175) mg·h/L, respectively. A one-compartment model with first-order elimination and absorption through transit compartments best described dolutegravir pharmacokinetics. For a typical 56 kg participant, we estimated a clearance, absorption rate constant, and volume of distribution of 1.87 L/h, 1.42 h
−1
, and 12.4 L, respectively. Each 10 mg·h/L increase in the AUC of coadministered rifampicin from 32.3 mg·h/L led to a 2.3 (3.1–1.4) % decrease in dolutegravir bioavailability. Genetic polymorphism of
UGT1A1
did not significantly affect dolutegravir pharmacokinetics. Simulations of trough dolutegravir concentrations show that the 50 mg twice-daily regimen attains both the primary and secondary therapeutic targets of 0.064 and 0.3 mg/L, respectively, regardless of the dose of coadministered rifampicin, unlike the once-daily regimen.
Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin
Authors: Kengo Allan , Gausi Kamunkhwala , Nabisere Ruth , Musaazi Joseph , Buzibye Allan , Omali Denis , Aarnoutse Rob , Lamorde Mohammed , Dooley Kelly E. , Sloan Derek James , Sekaggya-Wiltshire Christine , Denti Paolo
Published: October 2023

We characterized the pharmacokinetics of standard- and high-dose rifampicin in Ugandan adults with tuberculosis and HIV taking dolutegravir- or efavirenz-based antiretroviral therapy. A liver model with saturable hepatic extraction adequately described the data, and the increase in exposure between high and standard doses was 4.7-fold. This was lower than what previous reports of dose-exposure nonlinearity would predict and was ascribed to 38% lower bioavailability of the rifampicin-only top-up formulation compared to the fixed-dose combination.
Optimizing anidulafungin exposure across a wide adult body size range
Authors: Hall, Ronald G. , Liu Shuhan , Putnam William C. , Kallem Rajareddy , Gumbo Tawanda , Pai Manjunath P.
Published: October 2023

Echinocandins like anidulafungin are first-line therapies for candidemia and invasive candidiasis, but their dosing may be suboptimal in obese patients. Our objective was to quantify anidulafungin exposure in a cohort of adults across a wide body size range to test if body size affects anidulafungin pharmacokinetics (PK). We enrolled 20 adults between the ages of 18 and 80 years, with an equal distribution of patients above and below a body mass index of 30 kg/m
2
. A single 100-mg dose of anidulafungin was administered, followed by intensive sampling over 72 h. Population PK analysis was used to identify and compare covariates of anidulafungin PK parameters. Monte Carlo simulations were performed to compute the probability of target attainment (PTA) based on alternative dosing regimens. Participants (45% males) had a median (range) age of 45 (21–78) years and a median (range) weight of 82.7 (42.4–208.3) kg. The observed median (range) of AUC
0-∞
was 106.4 (51.9, 138.4) mg∙h/L. Lean body weight (LBW) and adjusted body weight (AdjBW) were more influential than weight as covariates of anidulafungin PK parameters. The conventional 100 mg daily maintenance is predicted to have a PTA below 90% in adults with an LBW > 55 kg or an AdjBW > 75 kg. A daily maintenance dose of 150–200 mg is predicted in these heavier adults. Anidulafungin AUC
0-∞
declines with increasing body size. A higher maintenance dose will increase the PTA compared to the current approach in obese patients.
Efficient modulation of cellular phosphorus components in response to phosphorus deficiency in the dinoflagellate
Karenia mikimotoi
Authors: Huang Xue-Ling , Zhuang Yan-Qing , Xiong Yue-Yue , Li Da-Wei , Ou Lin-Jian
Published: October 2023

With an increasing trend of phosphorus limitation in coastal waters, phytoplankton with advantageous strategies to address phosphorus deficiency might be more competitive in their communities. Combining physiological, transcriptomic, and miRNA analyses, the present study analyzed the molecular responses of different intracellular phosphorus components to phosphorus deficiency in the harmful dinoflagellate
Karenia mikimotoi
, with a specific focus on membrane phospholipid remodeling. The cellular phosphorus components of phospholipids, polyphosphate (polyP), and RNA and the associated gene expression showed dynamic variations over a prolonged phosphorus-stressed period. Under phosphorus deficiency,
K. mikimotoi
preferred to preserve polyP and RNA but efficiently replaced phospholipids with glycerol glycolipids and a betaine lipid to maintain active growth. This dynamic phospholipid substitution in
K. mikimotoi
was a combined result of the cessation of phospholipid biosynthesis and an increase in phospholipid breakdown. The expression of the identified miRNAs involved in ATP metabolism indicated that miRNAs may play an important role in regulating energy metabolism in
K. mikimotoi
. The present study improved the understanding of the molecular mechanism of intracellular phosphorus metabolism in marine phytoplankton and highlighted the strong capability of dinoflagellates to efficiently modulate intracellular phosphorus resources.

IMPORTANCE

Dinoflagellates are the most common phytoplankton group and account for more than 75% of harmful algal blooms in coastal waters. In recent decades, dinoflagellates seem to prevail in phosphate-depleted waters. However, the underlying acclimation mechanisms and competitive strategies of dinoflagellates in response to phosphorus deficiency are poorly understood, especially in terms of intracellular phosphorus modulation and recycling. Here, we focused on the response of intracellular phosphorus metabolism to phosphorus deficiency in the model dinoflagellate
Karenia mikimotoi
. Our work reveals the strong capability of
K. mikimotoi
to efficiently regulate intracellular phosphorus resources, particularly through membrane phospholipid remodeling and miRNA regulation of energy metabolism. Our research improved the understanding of intracellular phosphorus metabolism in marine phytoplankton and underscored the advantageous strategies of dinoflagellates in the efficient modulation of internal phosphorus resources to maintain active physiological activity and growth under unsuitable phosphorus conditions, which help them outcompete other species in coastal phosphate-depleted environments.
The DEAD-box RNA helicase RhlB is required for efficient RNA processing at low temperature in
Caulobacter
Authors: de Araújo Hugo L. , Picinato Beatriz A. , Lorenzetti Alan P. R. , Muthunayake Nisansala S. , Rathnayaka-Mudiyanselage I. W. , dos Santos Naara M. , Schrader Jared , Koide Tie , Marques Marilis V.
Published: October 2023

The RNA helicases from the DEAD-box family participate in several biochemical processes, with special relevance in the assembly of ribosome ribonucleoparticles and in RNA turnover as part of the multi-enzymatic RNA degradosome complex.
Caulobacter crescentus
has three DEAD-box RNA helicases, including RhlB, the main RNA helicase associated with the RNA degradosome. In this work, we evaluated the impact of RhlB on
C. crescentus
gene expression both at normal and low temperatures and its role in global RNA decay. The
rhlB
null mutant showed a freezing-sensitive phenotype after pre-incubation at low temperature, indicating a failure in assembling a proper cryotolerance response. A global transcriptomic profile of the wild-type and
rhlB
mutants was carried out at 30°C and 10°C and showed 73 and 477 differentially expressed genes, with the most affected gene categories being translation and posttranslational modifications. The
rhlB
mutant is more sensitive to streptonigrin, suggesting that the downregulation of iron-regulated genes may be due to a higher intracellular iron concentration. A high throughput screening for RhlB-binding RNAs identified 220 transcripts at 30°C, and global RNA decay analyses identified several mRNAs and sRNAs that displayed altered profiles of RNA decay rates. Analyses of the transcripts’ 5′-ends from the
C. crescentus rhlB
mutant and from
Pseudomonas aeruginosa
PAO1
rhlE1
and
rhlE2
mutants confirm that in the absence of the DEAD-box RNA helicase associated with RNase E, there is an accumulation of RNA degradation intermediates.

IMPORTANCE

One of the most important control points in gene regulation is RNA stability, which determines the half-life of a transcript from its transcription until its degradation. Bacteria have evolved a sophisticated multi-enzymatic complex, the RNA degradosome, which is dedicated mostly to RNA turnover. The combined activity of RNase E and the other RNA degradosome enzymes provides an efficient pipeline for the complete degradation of RNAs. The DEAD-box RNA helicases are very often found in RNA degradosomes from phylogenetically distant bacteria, confirming their importance in unwinding structured RNA for subsequent degradation. This work showed that the absence of the RNA helicase RhlB in the free-living Alphaproteobacterium
Caulobacter crescentus
causes important changes in gene expression and cell physiology. These are probably due, at least in part, to inefficient RNA processing by the RNA degradosome, particularly at low-temperature conditions.
Enhanced phagocytosis and complement-mediated killing of
Mannheimia haemolytica
serotype 1 following in-frame CMP-sialic acid synthetase (
neuA
) gene deletion
Authors: Menghwar Harish , Tatum Fred M. , Briggs Robert E. , Casas Eduardo , Kaplan Bryan S. , Azadi Parastoo , Dassanayake Rohana P.
Published: October 2023

Mannheimia haemolytica
is the most significant bacterial pathogen associated with the bovine respiratory disease complex. Although sialic acid is a known virulence factor in other members of Pasteurellaceae, such as
Histophilus somni
and
Pasteurella multocida
, the significance of sialic acid to the virulence of
M. haemolytica
is currently unknown. Therefore, the role of sialic acid as a virulence determinant of
M. haemolytica
was investigated by constructing an in-frame
neuA
[CMP-N-acetylneuraminic acid (Neu5Ac/sialic) synthetase] mutant, which was shown by high-performance anion exchange chromatographic analysis (HPAEC) to be devoid of sialic acid on the lipopolysaccharide (LPS). Both the
neuA
mutant and wild-type parent strains exhibited similar growth rates in the growth curve assay. Real-time qPCR and ELISA evaluation showed no differences in proinflammatory cytokine expressions (IL-1β, IL-6, and IL-8) between the
neuA
mutant and parent strain when peripheral blood mononuclear cells were incubated with LPS. Interestingly, the
neuA
mutant was three to four logs more sensitive to a whole-blood bacterial killing assay than the parent strain. Similar results were also observed in plasma and serum bacterial killing assays. Flow cytometry analyses showed higher uptake of
neuA
mutant by phagocytes, compared to the parent strain, in the whole-blood phagocytosis assay; however, no difference in reactive oxygen species production in neutrophils or monocytes was detected for either strain. Taken together, these results indicate that sialylation of
M. haemolytica
LPS plays a vital role in reducing complement-mediated and phagocytic killing.

IMPORTANCE

The Gram-negative coccobacillus
Mannheimia haemolytica
is a natural inhabitant of the upper respiratory tract in ruminants and the most common bacterial agent involved in bovine respiratory disease complex development. Key virulence factors harbored by
M. haemolytica
are leukotoxin, lipopolysaccharide, capsule, adhesins, and neuraminidase which are involved in evading innate and adaptive immune responses. In this study, we have shown that CMP-sialic acid synthetase (
neuA
) is necessary for the incorporation of sialic acid onto the membrane, and inactivation of
neuA
results in increased phagocytosis and complement-mediated killing of
M. haemolytica,
thus demonstrating that sialylation contributes to the virulence of
M. haemolytica
.
Rhabdomyolysis in McArdle disease caused by scuba diving
Authors: McCann Ulysse George , Park Thomas
Published: October 2023

McArdle disease is a glycogen storage disease that results in rhabdomyolysis during intense exercise. A number of different triggers have been described. We evaluated a patient with McArdle disease who presented with rhabdomyolysis after recreational scuba diving. There was no concern for barotrauma or decompression sickness. His symptoms resolved with standard-of-care management for non-diving-related rhabdomyolysis. Features of his experience provoked questions about the diving-related factors contributing to his presentation. We present the case and explore possible mechanisms of diving-related injury in patients with McArdle disease, including the possible effects of hyperoxia, hyperbaria, hypothermia and strenuous activity.
Hydrocele and endometriosis of the canal of Nuck in two adults: a look at the imaging features
Authors: Singh Anmol , Chauhan Ekta , Kalantri Amrita , Gupta Sanjay
Published: October 2023

We present a report of two adult females who presented to the surgery clinic at different time frames in our hospital with a swelling in the inguinal region. The swelling was painful for one of our patients. The first patient was evaluated with a contrast-enhanced CT and an MRI, while the second patient underwent a ultrasonography and an MRI. Imaging revealed the structure to be cystic in nature and confirmed the diagnosis as a hydrocele of the canal of Nuck in both patients. Our second patient was also found to have concomitant endometriosis, with internal septations seen in the hydrocele. Aspiration revealed altered blood with haemosiderin deposition, which established a diagnosis of endometriosis of the canal of Nuck. The first patient underwent excision, while the second patient refused a surgical approach and opted for medical management for endometriosis.
Automated classification of multiple ophthalmic diseases using ultrasound images by deep learning
Authors: Wang Yijie , Xu Zihao , Dan Ruilong , Yao Chunlei , Shao Ji , Sun Yiming , Wang Yaqi , Ye Juan
Published: October 2023

Background

Ultrasound imaging is suitable for detecting and diagnosing ophthalmic abnormalities. However, a shortage of experienced sonographers and ophthalmologists remains a problem. This study aims to develop a multibranch transformer network (MBT-Net) for the automated classification of multiple ophthalmic diseases using B-mode ultrasound images.

Methods

Ultrasound images with six clinically confirmed categories, including normal, retinal detachment, vitreous haemorrhage, intraocular tumour, posterior scleral staphyloma and other abnormalities, were used to develop and evaluate the MBT-Net. Images were derived from five different ultrasonic devices operated by different sonographers and divided into training set, validation set, internal testing set and temporal external testing set. Two senior ophthalmologists and two junior ophthalmologists were recruited to compare the model’s performance.

Results

A total of 10 184 ultrasound images were collected. The MBT-Net got an accuracy of 87.80% (95% CI 86.26% to 89.18%) in the internal testing set, which was significantly higher than junior ophthalmologists (95% CI 67.37% to 79.16%; both p<0.05) and lower than senior ophthalmologists (95% CI 89.45% to 92.61%; both p<0.05). The micro-average area under the curve of the six-category classification was 0.98. With reference to comprehensive clinical diagnosis, the measurements of agreement were almost perfect in the MBT-Net (kappa=0.85, p<0.05). There was no significant difference in the accuracy of the MBT-Net across five ultrasonic devices (p=0.27). The MBT-Net got an accuracy of 82.21% (95% CI 78.45% to 85.44%) in the temporal external testing set.

Conclusions

The MBT-Net showed high accuracy for screening and diagnosing multiple ophthalmic diseases using only ultrasound images across mutioperators and mutidevices.