bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors associated with prolonged episodes of mechanical restraint in mental health hospitalization units in Andalusia
Authors: Guzmán‐Parra José , Aguilera‐Serrano Carlos , Huizing Evelyn , Bono del Trigo Aguila , Villagrán José María , Hurtado Melero Verónica , García‐Sanchez Juan Antonio , Mayoral‐Cleries Fermín
Published: January 2022

Accessible Summary

What is known on the subject?

Risk factors associated with prolonged episodes of mechanical restraint and other coercive measures are understudied.

There have been no studies of this phenomenon in the context of the Andalusian public health system.

Knowledge about factors associated with prolonged episodes is essential to increase the understanding of this phenomenon and develop strategies to reduce its occurrence.

What does this paper add to existing knowledge?

In Andalusia, prolonged restraint is still frequent and varies depending on the unit.

It is associated with less time since admission, male gender, diagnosis, reason for restraint and the shift on which it was initiated.

What are the implications for practice?

Interventions at the level of the units could be necessary to prevent prolonged episodes of mechanical restraint.

The results suggest the need for stricter control during the shifts on which restraint starts, especially in the first days after the patient's admission.

Preventive risk assessment considering clinical and sociodemographic risk factors could help to reduce prolonged restraint.

Introduction

Factors associated with prolonged episodes of mechanical restraint and other coercive interventions are not clearly established and have been not studied in Andalusia (Spain).

Aim

To study factors associated with prolonged episodes of mechanical restraint.

Method

We analysed retrospectively episodes of mechanical restraint (N = 6267, prolonged episode >9.5 hours) in all public mental health hospitalization units (N = 20, 535 beds) that offer health coverage for the autonomous community of Andalusia. The data came from clinical records. A multivariable mixed logistic regression was used.

Results

In Andalusia, prolonged restraint is still frequent and varies depending on the unit. It is associated with less time since admission, male gender, diagnosis, reason for restraint and the shift on which it was initiated.

Discussion

The results provide evidence that prolonged episodes largely depend on the unit where they occur and that stricter control and regulation are necessary to prevent prolonged episodes.

Implications for practice

Interventions at the level of the unit are necessary. Stricter control in the shifts during which there is more risk of prolonged restraint may be necessary, especially in the first days following admission.
Implied license doctrine in copyright law: A typological framework
Authors: Zhang Hongjiao , Chen Fanhong
Published: January 2022

To strike the post‐grant balance of interests between copyright owners and users, this paper defines three normative types of implied licenses. The typological framework recognizes a hierarchical degree of deference to copyright owners' intent, such that its function varies from the high degree of deference in the opt‐in system to the intermediate degree of the opt‐out system, down to the lowest degree of the nonoption system. The three systems in this framework, working on a sliding scale, reflect and further the flexibility of the doctrine. Moreover, given the complexity of weighing the conflicting interests of copyright owners and users, a prescription for elements to be considered, taken from existing cases and the function of the doctrine, is required to slide the application of the doctrine from one type to another. In this way, a greater degree of certainty of the doctrine is improved and the predictability of judicial decisions is increased.
Structural Advocacy Organizations and Intersectional Outcomes: Effects of Women's Police Stations on Female Homicides
Authors: Arvate Paulo , Cabral Sandro , Mcgahan Anita M. , Reis Paulo Ricardo
Published: January 2022

By introducing the concept of “structural advocacy organizations,” this study theorizes and tests the boundary conditions within which organizations designed to protect the rights of disenfranchised groups promote structural changes at the intersection of gender and race. We test these claims on Brazil's “women's police stations,” a type of structural advocacy organization with greater female representation on staff and with specialized procedures and an institutional mandate to address violence against women. The analysis indicates that homicides are lower among the population of women in municipalities which have women's police stations. However, within this group, homicides committed against women who self‐identify as “black” and “brown” are lower only in municipalities that are characterized by high levels of female education and in metropolitan areas with infrastructure development. The results suggest that improving intersectional outcomes for women who are disenfranchised on race requires complementary policies and institutional mandates to address racialized violence.
Trade‐offs and the precautionary principle: A lexicographic utility approach
Authors: Steel Daniel , Bartha Paul
Published: January 2022

The precautionary principle is often argued to be irrational because it cannot adequately explain how resources should be distributed across multiple possible catastrophes or between catastrophic and noncatastrophic risks. We address this problem of trade‐offs by extending a recently proposed formal interpretation of the precautionary principle (PP) within a lexical utility framework and using it to prove results about which distribution of resources maximizes lexical utility when several catastrophic risks exist, given different assumptions. We also explain how our lexical utility interpretation of PP can recommend balanced distributions of resources between disaster prevention and other concerns.
A review of electronic medical records and safe transfusion practice for guideline development
Authors: Crispin Philip , Akers Christine , Brown Kristen , Delaforce Alana , Keegan Anastazia , King Fiona , Ormerod Amanda , Verrall Trudi
Published: January 2022

Background and Objectives

Electronic medical records (EMRs) are often composed of multiple interlinking systems, each serving a particular task, including transfusion ordering and administration. Transfusion may not be prioritized when developing or implementing electronic platforms. Uniform guidelines may assist information technology (IT) developers, institutions and healthcare workforces to progress with shared goals.

Materials and Methods

A narrative review of current clinical guidance, benefits and risks of electronic systems for clinical transfusion practice was combined with feedback from experienced transfusion practitioners.

Results

There is opportunity to improve the safety, quality and efficiency of transfusion practice, particularly through decision support and better identification procedures, by incorporating transfusion practice into EMRs. However, these benefits should not be assumed, as poorly designed processes within the electronic systems and the critically important electronic–human process interfaces may increase risk while creating the impression of safety.

Conclusion

Guidelines should enable healthcare and IT industries to work constructively together so that each implementation provides assurance of safe practice.
Quantitative Analyses of Collective Cell Motion on the Patterned Surfaces
Authors: Xu Xiangyu , Xu Jiayi , Li Xiaojun , Song Jizhou , Li Dechang , Ji Baohua
Published: January 2022

Collective cell motion is crucial for various physiological and pathological processes, and it highly relies on physical factors in cell microenvironment. However, a quantitative understanding of the effect of the physical factors remains lacking. Here, we studied the collective motion of cells on patterned matrixes with experimental study and numerical simulation by quantitatively analyzing the features of cell collective motion. We found that the collectivity of cell motion is size-dependent. The cells have high collectivity on a small pattern, while they lose the collectivity on the large one. The geometry of the pattern also influences the collective motion by regulating the velocity distribution in the cell layer. Interestingly, the cell density can significantly influence the collective motion by changing the active stress of the cells. For a quantitative understanding of the mechanisms of the effect of these physical factors, we adopted a coarse-grained cell model that considers the active contraction of cells by introducing cell active stress in the model based on the traction-distance law. Our numerical simulation predicted not only the cell velocity, cell collectivity, and cell polarization, but also the stress distribution in the cell layer. The consistency between the numerical predictions and experimental results reveals the relationship between the pattern of collective cell motion and the stress distribution in the cell layer, which sheds light on the studies of tissue engineering for biomedical applications.
Parameter Identification of an Abrasive Manufacturing Process With Machine Learning of Measured Surface Topography Information
Authors: Schmidt Samuel , Eifler Matthias , Issel Jan Cedric , de Payrebrune Kristin M. , Ströer Felix , Karatas Abdullah , Seewig Jörg
Published: January 2022

The correlation between manufacturing parameters and the resulting surface topography is most often described with standardized profile surface texture parameters (R-parameters). However, in many cases, they represent a strong simplification as the most common parameters are often neither function-oriented nor unambiguously correlated with the manufacturing parameters. Therefore, we investigate whether a neural network is a suitable alternative to establish a more comprehensive correlation between the surface topography and the manufacturing parameters. The learned correlation provides possibilities to be used for subsequent monitoring of the manufacturing process. Our approach is to predict the manufacturing parameters from a measured topography dataset with a convolutional neural network as a regression model. As the training of neural networks requires large amounts of data, stochastic surface models are applied to generate artificial profiles and thus increase the available amount of data. The prediction accuracy and consequently its correlation with the manufacturing parameters are evaluated for a case study of an abrasive process. In this case study, it is first determined whether artificial or measured profiles and which of their representations (frequency or time dependent) provide the best information to train the network. The network featuring the most reliable prediction of the manufacturing parameters is then used for further analysis. By comparing this network with a linear regression model between manufacturing parameters and R-parameters, its performance is benchmarked and can be suggested as a suitable alternative to predict and monitor manufacturing parameters based on the measured surface topography.
Using Physics-Informed Generative Adversarial Networks to Perform Super-Resolution for Multiphase Fluid Simulations
Authors: Li Matthew , McComb Christopher
Published: January 2022

Computational fluid dynamics (CFD) simulations are useful in the field of engineering design as they provide deep insights on product or system performance without the need to construct and test physical prototypes. However, they can be very computationally intensive to run. Machine learning methods have been shown to reconstruct high-resolution single-phase turbulent fluid flow simulations from low-resolution inputs. This offers a potential avenue towards alleviating computational cost in iterative engineering design applications. However, little work thus far has explored the application of machine learning image super-resolution methods to multiphase fluid flow (which is important for emerging fields such as marine hydrokinetic energy conversion). In this work, we apply a modified version of the super-resolution generative adversarial network (SRGAN) model to a multiphase turbulent fluid flow problem, specifically to reconstruct fluid phase fraction at a higher resolution. Two models were created in this work, one which incorporates a physics-informed term in the loss function and one which does not, and the results are discussed and compared. We found that both models significantly outperform non-machine learning upsampling methods and can preserve a substantial amount of detail, showing the versatility of the SRGAN model for upsampling multiphase fluid simulations. However, the difference in accuracy between the two models is minimal indicating that, in the context studied here, the additional complexity of a physics-informed approach may not be justified.
Roll–Yaw Lock: Aerodynamic Motion Instabilities of Floating Offshore Wind Turbines
Authors: Haslum Herbjørn , Marley Mathias , Navalkar Sachin Tejwant , Skaare Bjørn , Maljaars Nico , Andersen Haakon S.
Published: January 2022

This article presents an investigation of a newly discovered motion instability phenomenon for floating wind turbines, first observed in numerical aero-hydro-servo-elastic simulations. The source of instability is identified as antisymmetric aerodynamic stiffness coupling terms in roll and yaw caused by the turbine thrust force. Analytical expressions for the roll–yaw and yaw–roll stiffness coupling terms are derived, using the actuator disk analogy of the rotor plane. It is demonstrated that a two degrees-of-freedom linear equation of motion without explicit external forcing qualitatively captures the instability. Based on this model, an analytical stability criteria is derived. An intuitive physical explanation of the phenomena is provided, considering the energy flow of the system. An important finding is that dissipative forces, in the form of aerodynamic and hydrodynamic damping, are needed to fully explain the observed instability. It is demonstrated, counterintuitively, that increased damping in yaw reduces the stability margin. This is explained by the fact that dissipative forces result in a phase difference between the harmonic roll and yaw motion in the coupled roll–yaw modes.
Lubrication Characteristics of Water-Lubricated Rubber Bearings Based on an Improved Algorithm of the Mass Conservation Boundary Condition
Authors: Liu Gang , Li Ming
Published: January 2022

Water-lubricated rubber bearings (WLRBs) are widely used in the propulsion systems of ships and military crafts. Based on the mass conservation boundary condition, the elastohydrodynamic lubrication model of WLRBs is established after considering the elastic deformation of the rubber liner and solved by the finite difference method. An improved algorithm is proposed to track the mass conservation boundary. For the first time, the algorithm allocates independent finite difference grids for the film pressure and fluid fraction to overcome the instability issues and to ensure the flow conservation of each grid cell. The accuracy and stability of the algorithm are verified by the experimental data in the literature, comparison of film pressures calculated by two different finite difference schemes, and flowrate calculations of two different bearings. The lubrication characteristics under the mass conversation boundary condition are compared with classical boundary conditions. The results indicate that the film pressure distribution, velocity distribution, and size and shape of the cavitation zone vary greatly under different boundary conditions in the clearance divergence region. The bearing capacity, attitude angle, and friction force under the mass conservation boundary condition are the largest; those under the double Reynolds boundary condition are smaller; and those under the Reynolds boundary condition are the smallest.
Characterization of Annular Cement Permeability of a Logged Well Section Using Pressure–Pulse Decay Measurements
Authors: Skadsem Hans Joakim
Published: January 2022

The cement behind casings is an important barrier element in wells that should provide zonal isolation along the well. The hardened cement does not always isolate permeable formations, either due to placement issues or loads that over time compromise the integrity of the barrier. The modern method used to characterize the annular material is ultrasonic logging which provides essential information concerning the type of material behind casing, but no measurement of the annular permeability. This study provides permeability characterization of a casing-cement sandwich joint retrieved from a 33 years old production well that has been logged at surface using a state-of-the-art ultrasonic tool. The joint contains an interval of low-permeable cement that previously has prevented permeability measurement by gas injection. A pressure–pulse decay test method has now been performed that is based on monitoring the evolution of a pressure pulse through the joint. Long-term pressure measurements show communication through the entire joint and are in qualitative agreement with the log. A pressure diffusion model is used to estimate local permeability along the joint, enabling comparison of log response and permeability. The low-permeable region is relatively short, situated directly on top of a casing collar, and has permeability that is orders of magnitude lower than the cement above and below. In the longer term, results from this and related studies can be used as input for future sustained casing pressure evaluations or for quantifying seepage risk behind casings for abandonment designs.
A new species and a new report of Cunaxoidinae for the Brazil (Acari: Cunaxidae)
Authors: Wurlitzer Wesley Borges , Ferla Noeli Juarez , Franklin Elizabeth , Rocha Matheus dos Santos
Published: January 2022

We describe adults of a new species, namely Lupaeus brasiliensis Wurlitzer & Rocha sp. nov., and report the first occurrence of Pulaeus krama (Chaudhri, 1977) from the Brazilian Amazon Rainforest.
Oxygen incorporation in AlN films grown by plasma-enhanced atomic layer deposition
Authors: Gungor Nese , Alevli Mustafa
Published: January 2022

Oxygen is often detected as an impurity in III-nitride films deposited by atomic layer deposition (ALD). The presence of oxygen has deep and unfavorable influences on the structural and optical properties of AlN. We have studied the oxygen incorporation in AlN films prepared by hollow cathode plasma-assisted ALD by alternating H2 plasma. We report a decrease in the O concentration in the film upon the addition of H2 plasma flow. However, increasing the H2 plasma flow does not further decrease the O incorporation. Film composition became almost constant at the surface and beneath the surface of AlN films deposited using N2/H2 plasma. Only samples grown with N2/H2 plasma showed decreases in oxygen concentration from the surface to the bulk film. Oxygen produces important modifications in the structural, chemical, and electrical properties. The Al 2p, N 1s, and O 1s high-resolution x-ray photoelectron spectra represent that AlN films are composed of Al–N, Al–O, and N–Al–O bonds. X-ray photoelectron spectroscopy data suggest that the composition of the AlN film changes to AlON + AlN when N2 plasma is used. The valence band maximum position of the AlN film is found to be at ∼1.7 eV for oxygen atomic concentration ∼20 at. %. The TO and LO phonon modes are present in AlN films with oxygen contamination ∼20 at. % and disappear at high oxygen contamination (∼55 at. %).
Predicting synapse counts in living humans by combining computational models with auditory physiology
Authors: Buran Brad N. , McMillan Garnett P. , Keshishzadeh Sarineh , Verhulst Sarah , Bramhall Naomi F.
Published: January 2022

Aging, noise exposure, and ototoxic medications lead to cochlear synapse loss in animal models. As cochlear function is highly conserved across mammalian species, synaptopathy likely occurs in humans as well. Synaptopathy is predicted to result in perceptual deficits including tinnitus, hyperacusis, and difficulty understanding speech-in-noise. The lack of a method for diagnosing synaptopathy in living humans hinders studies designed to determine if noise-induced synaptopathy occurs in humans, identify the perceptual consequences of synaptopathy, or test potential drug treatments. Several physiological measures are sensitive to synaptopathy in animal models including auditory brainstem response (ABR) wave I amplitude. However, it is unclear how to translate these measures to synaptopathy diagnosis in humans. This work demonstrates how a human computational model of the auditory periphery, which can predict ABR waveforms and distortion product otoacoustic emissions (DPOAEs), can be used to predict synaptic loss in individual human participants based on their measured DPOAE levels and ABR wave I amplitudes. Lower predicted synapse numbers were associated with advancing age, higher noise exposure history, increased likelihood of tinnitus, and poorer speech-in-noise perception. These findings demonstrate the utility of this modeling approach in predicting synapse counts from physiological data in individual human subjects.
Modulating environmental signals to reveal mechanisms and vulnerabilities of cancer persisters
Authors: Sun Xiaoxiao , Bieber Jake M. , Hammerlindl Heinz , Chalkley Robert J. , Li Kathy H. , Burlingame Alma L. , Jacobson Matthew P. , Wu Lani F. , Altschuler Steven J.
Published: January 2022

Cancer persister cells are able to survive otherwise lethal doses of drugs through nongenetic mechanisms, which can lead to cancer regrowth and drug resistance. The broad spectrum of molecular differences observed between persisters and their treatment-naïve counterparts makes it challenging to identify causal mechanisms underlying persistence. Here, we modulate environmental signals to identify cellular mechanisms that promote the emergence of persisters and to pinpoint actionable vulnerabilities that eliminate them. We found that interferon-γ (IFNγ) can induce a pro-persistence signal that can be specifically eliminated by inhibition of type I protein arginine methyltransferase (PRMT) (PRMTi). Mechanistic investigation revealed that signal transducer and activator of transcription 1 (STAT1) is a key component connecting IFNγ’s pro-persistence and PRMTi’s antipersistence effects, suggesting a previously unknown application of PRMTi to target persisters in settings with high STAT1 expression. Modulating environmental signals can accelerate the identification of mechanisms that promote and eliminate cancer persistence.
Local contractions regulate E-cadherin rigidity sensing
Authors: Yang Yi-An , Nguyen Emmanuelle , Sankara Narayana Gautham Hari Narayana , Heuzé Melina , Fu Chaoyu , Yu Hanry , Mège René-Marc , Ladoux Benoit , Sheetz Michael P.
Published: January 2022

E-cadherin is a major cell-cell adhesion molecule involved in mechanotransduction at cell-cell contacts in tissues. Because epithelial cells respond to rigidity and tension in tissue through E-cadherin, there must be active processes that test and respond to the mechanical properties of these adhesive contacts. Using submicrometer, E-cadherin–coated polydimethylsiloxane pillars, we find that cells generate local contractions between E-cadherin adhesions and pull to a constant distance for a constant duration, irrespective of pillar rigidity. These cadherin contractions require nonmuscle myosin IIB, tropomyosin 2.1, α-catenin, and binding of vinculin to α-catenin. Cells spread to different areas on soft and rigid surfaces with contractions, but spread equally on soft and rigid without. We further observe that cadherin contractions enable cells to test myosin IIA–mediated tension of neighboring cells and sort out myosin IIA–depleted cells. Thus, we suggest that epithelial cells test and respond to the mechanical characteristics of neighboring cells through cadherin contractions.
Acylhydrazine-based reticular hydrogen bonds enable robust, tough, and dynamic supramolecular materials
Authors: Deng Yuanxin , Zhang Qi , Shi Chenyu , Toyoda Ryojun , Qu Da-Hui , Tian He , Feringa Ben L.
Published: January 2022

Supramolecular materials are widely recognized among the most promising candidates for future generations of sustainable plastics because of their dynamic functions. However, the weak noncovalent cross-links that endow dynamic properties usually trade off materials’ mechanical robustness. Here, we present the discovery of a simple and robust supramolecular cross-linking strategy based on acylhydrazine units, which can hierarchically cross-link the solvent-free network of poly(disulfides) by forming unique reticular hydrogen bonds, enabling the conversion of soft into stiff dynamic material. The resulting supramolecular materials exhibit increase in stiffness exceeding two to three orders of magnitude compared to those based on the hydrogen-bonding network of analogous carboxylic acids, simultaneously preserving the repairability, malleability, and recyclability of the materials. The materials also show high adhesion strength on various surfaces while allowing multiple surface attachment cycles without fatigue, illustrating a viable approach how robustness and dynamics can be merged in future material design.
Nanospike electrodes and charge nanoribbons: A new design for nanoscale thin-film transistors
Authors: Liang Kelly , Xu Xin , Zhou Yuchen , Wang Xiao , McCulley Calla M. , Wang Liang , Kulkarni Jaydeep , Dodabalapur Ananth
Published: January 2022

To scale down thin-film transistor (TFT) channel lengths for accessing higher levels of speed and performance, a redesign of the basic device structure is necessary. With nanospike-shaped electrodes, field-emission effects can be used to assist charge injection from the electrodes in sub–200-nm channel length amorphous oxide and organic TFTs. These designs result in the formation of charge nanoribbons at low gate biases that greatly improve subthreshold and turn-off characteristics. A design paradigm in which the gate electric field can be less than the source-drain field is proposed and demonstrated. By combining small channel lengths and thick gate dielectrics, this approach is also shown to be a promising solution for boosting TFT performance through charge focusing and charge nanoribbon formation in flexible/printed electronics applications.
Administration of aerosolized SARS-CoV-2 to K18-hACE2 mice uncouples respiratory infection from fatal neuroinvasion
Authors: Fumagalli Valeria , Ravà Micol , Marotta Davide , Di Lucia Pietro , Laura Chiara , Sala Eleonora , Grillo Marta , Bono Elisa , Giustini Leonardo , Perucchini Chiara , Mainetti Marta , Sessa Alessandro , Garcia-Manteiga José M. , Donnici Lorena , Manganaro Lara , Delbue Serena , Broccoli Vania , De Francesco Raffaele , D’Adamo Patrizia , Kuka Mirela , Guidotti Luca G. , Iannacone Matteo
Published: January 2022

The development of a tractable small animal model faithfully reproducing human coronavirus disease 2019 pathogenesis would arguably meet a pressing need in biomedical research. Thus far, most investigators have used transgenic mice expressing the human ACE2 in epithelial cells (K18-hACE2 transgenic mice) that are intranasally instilled with a liquid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suspension under deep anesthesia. Unfortunately, this experimental approach results in disproportionate high central nervous system infection leading to fatal encephalitis, which is rarely observed in humans and severely limits this model’s usefulness. Here, we describe the use of an inhalation tower system that allows exposure of unanesthetized mice to aerosolized virus under controlled conditions. Aerosol exposure of K18-hACE2 transgenic mice to SARS-CoV-2 resulted in robust viral replication in the respiratory tract, anosmia, and airway obstruction but did not lead to fatal viral neuroinvasion. When compared with intranasal inoculation, aerosol infection resulted in a more pronounced lung pathology including increased immune infiltration, fibrin deposition, and a transcriptional signature comparable to that observed in SARS-CoV-2–infected patients. This model may prove useful for studies of viral transmission, disease pathogenesis (including long-term consequences of SARS-CoV-2 infection), and therapeutic interventions.
Supplemental Material: Assessing the effect of melt extraction from mushy reservoirs on compositions of granitoids: From a global database to a single batholith
Authors: Cornet J. , al. et
Published: January 2022

Includes database with matched compositions for bulk plutonic rocks and associated minerals; detailed tutorial for using iSpectra®; and more exhaustive set of simulations.
Supplemental Material: Rapid sediment re-deposition may limit carbon release during catastrophic thermokarst lake drainage
Authors: Burnham Brian S. , al. et
Published: January 2022

Table S1: Geometric measurements obtained from satellite imagery of rapidly drained thermokarst lakes and associated deltas and thermo-erosion gullies. Lake ID relate to drained lakes identified in Nitze et al. (2020). Table S2: Estimated soil organic carbon content measured in gigagram (Gg) in top 2 m removed from thermo-erosion gullies. Estimates and approximate spatial resolution are derived from spatial statistical models presented in Zhu and McGuire (2016).
Severe neonatal hyperbilirubinaemia: lessons learnt from a national perinatal audit
Authors: van der Geest Berthe A M , Rosman Ageeth N , Bergman Klasien A , Smit Bert J , Dijk Peter H , Been Jasper V , Hulzebos Christian V
Published: January 2022

Objectives

To describe characteristics of neonates with severe neonatal hyperbilirubinaemia (SNH) and to gain more insight in improvable factors that may have contributed to the development of SNH.

Design and setting

Descriptive study, based on national Dutch perinatal audit data on SNH from 2017 to 2019.

Patients

Neonates, born ≥35 weeks of gestation and without antenatally known severe blood group incompatibility, who developed hyperbilirubinaemia above the exchange transfusion threshold.

Main outcome measures

Characteristics of neonates having SNH and corresponding improvable factors.

Results

During the 3-year period, 109 neonates met the eligibility criteria. ABO antagonism was the most frequent cause (43%). All neonates received intensive phototherapy and 30 neonates (28%) received an exchange transfusion. Improvable factors were mainly related to lack of knowledge, poor adherence to the national hyperbilirubinaemia guideline, and to incomplete documentation and insufficient communication of the a priori hyperbilirubinaemia risk assessment among healthcare providers. A priori risk assessment, a key recommendation in the national hyperbilirubinaemia guideline, was documented in only six neonates (6%).

Conclusions

SNH remains a serious threat to neonatal health in the Netherlands. ABO antagonism frequently underlies SNH. Lack of compliance to the national guideline including insufficient a priori hyperbilirubinaemia risk assessment, and communication among healthcare providers are important improvable factors. Implementation of universal bilirubin screening and better documentation of the risk of hyperbilirubinaemia may enhance early recognition of potentially dangerous neonatal jaundice.
Extracellular Hsp90α, which participates in vascular inflammation, is a novel serum predictor of atherosclerosis in type 2 diabetes
Authors: Ding Xinyi , Meng Chuzhen , Dong Hangming , Zhang Shili , Zhou Hui , Tan Wenchong , Huang Lei , He Aiping , Li Jieyou , Huang Jiali , Li Wei , Zou Fei , Zou MengChen
Published: January 2022

Introduction

Atherosclerosis is the main pathological change in diabetic angiopathy, and vascular inflammation plays an important role in early atherosclerosis. Extracellular heat shock protein 90 (eHsp90) is secreted into the serum and is involved in various physiological and pathophysiological processes. However, the specific mechanism of eHsp90 in early atherosclerosis remains unclear. This study explored the relationship between Hsp90 and diabetic lower extremity arterial disease and investigated the expression of eHsp90 in vascular endothelial cells under environmental stimulation and the function and mechanism of eHsp90α involved in diabetic atherosclerosis.

Research design and methods

One hundred and three selected patients were divided into three groups: the diabetes mellitus group (n=27), the diabetic lower extremity arterial disease group (n=46), and the diabetic critical limb ischemia group (n=30). The relationships among serum Hsp90, oxidative stress indexes, and patient outcomes and the correlations among the indexes were analyzed. H&E staining and immunohistochemistry were used to observe the vasculature of amputated feet from patients with diabetic foot. An oxidative stress endothelial injury model was established under high glucose in vitro to explore the role of eHsp90 release in atherosclerosis progression.

Results

The level of serum Hsp90 was upregulated with aggravation of diabetic vascular disease. Hsp90α was correlated with malondialdehyde to some extent and was an independent risk factor in the progression of diabetic vascular disease, with predictive ability. The expression area of Hsp90α was consistent with the area of inflammatory infiltration in the vessel lumen. Vascular endothelial cells were found to increase eHsp90α secretion under stress. Then inhibition of eHsp90α can reduce the degree of cellular inflammation and damage. Endothelial cell-conditioned medium and recombinant human Hsp90α increased monocyte migration via the low-denisity lipoprotein receptor-related protein 1 (LRP1) receptor to promote disease progression.

Conclusions

eHsp90α plays a critical role in the early inflammatory injury stage of atherosclerosis.

Trial registration number

NCT04787770.
Application of liquid biopsy-based targeted capture sequencing analysis to improve the precision treatment of non-small cell lung cancer by tyrosine kinase inhibitors
Authors: Zhang Lei , Coffin John , Formenti Kim , Chu Quincy , Izevbaye Iyare
Published: January 2022

Background

Targeted therapy of patients with non-small cell lung cancer (NSCLC) who harbour sensitising mutations by tyrosine kinase inhibitors (TKIs) has been found more effective than traditional chemotherapies. However, target genes status (eg, epidermal growth factor receptor (EGFR) TKIs sensitising and resistant mutations) need to be tested for choosing appropriate TKIs. This study is to investigate the performance of a liquid biopsy-based targeted capture sequencing assay on the molecular analysis of NSCLC.

Methods

Plasma samples from patients with NSCLC who showed resistance to the first/second-generationEGFRTKIs treatment were collected. The AVENIO ctDNA Expanded Kit is a 77 pan-cancer genes detection assay that was used for detectingEGFRTKIs resistance-associated gene mutations. Through comparison of theEGFRgene testing results from the CobasEGFRMutation Test v2, and UltraSEEK Lung Panel, the effectiveness of the targeted capture sequencing assay was verified.

Results

A total of 24 plasma cell-free DNA (cfDNA) samples were tested by the targeted capture sequencing assay. 33.3% (8/24) cfDNA samples were positive forEGFRexon 20 p.T790M which leads toEGFRdependent TKIs resistance. 8.3% (2/24) and 4.2% (1/24) samples were positive for mesenchymal-epithelial transition gene amplification and B‐Raf proto‐oncogene, serine/threonine kinase exon 15 p.V600E mutations which lead toEGFRindependent TKIs resistance. The median value of the p.T790M variant allele fraction and variant copy numbers was 2% and 36.10 copies/mL plasma, respectively. The next-generation sequencing test showed higher than 90% concordance with either MassArray or qPCR-based methods for detecting eitherEGFRTKIs sensitising or resistance mutations.

Conclusion

The targeted capture sequencing test can support comprehensive molecular analysis needed for TKIs treatment, which is promising to be clinically applied for the improved precision treatment of NSCLC.
Toll-like receptor 8 agonists improve NK-cell function primarily targeting CD56brightCD16−subset
Authors: Veneziani Irene , Alicata Claudia , Pelosi Andrea , Landolina Nadine , Ricci Biancamaria , D'Oria Valentina , Fagotti Anna , Scambia Giovanni , Moretta Lorenzo , Maggi Enrico
Published: January 2022

Background

Toll-like receptors (TLRs) are pattern-recognition sensors mainly expressed in innate immune cells that directly recognize conserved pathogen structures (pathogen-associated molecular patterns-PAMPs). Natural killer (NK) cells have been described to express different endosomal TLRs triggered by RNA and DNA sequences derived from both viruses and bacteria. This study was addressed to establish which endosomal TLR could directly mediate NK activation and function after proper stimuli. It was also important to establish the most suitable TLR agonist to be used as adjuvant in tumor vaccines or in combined cancer immunotherapies.

Methods

We assessed endosomal TLR expression in total NK cells by using RT-qPCR and western blotting technique. In some experiments, we purified CD56brightCD16−and CD56dimCD16+cells subsets by using NK Cell Isolation Kit Activation marker, cytokine production, CD107a expression and cytotoxicity assay were evaluated by flow cytometry. Cytokine release was quantified by ELISA. NK cells obtained from ovarian ascites underwent the same analyses.

Results

Although the four endosomal TLRs (TLR3, TLR7/8, and TLR9) were uniformly expressed on CD56brightCD16−and CD56dimCD16+cell subsets, the TLR7/8 (R848), TLR3 (polyinosinic-polycytidylic acid, Poly I:C) and TLR9 (ODN2395) ligands promoted NK-cell function only in the presence of suboptimal doses of cytokines, including interleukin (IL)-2, IL-12, IL-15, and IL-18, producedin vivoby other environmental cells. We showed that R848 rather than TLR3 and TLR9 agonists primarily activated CD56brightCD16−NK cells by increasing their proliferation, cytokine production and cytotoxic activity. Moreover, we demonstrated that R848, which usually triggers TLR7 and TLR8 on dendritic cells, macrophages and neutrophils cells, activated CD56brightCD16−NK-cell subset only via TLR8. Indeed, specific TLR8 but not TLR7 agonists increased cytokine production and cytotoxic activity of CD56brightCD16−NK cells. Importantly, these activities were also observed in peritoneal NK cells from patients with metastatic ovarian carcinoma, prevalently belonging to the CD56brightCD16−subset.

Conclusion

These data highlight the potential value of TLR8 in NK cells as a new target for immunotherapy in patients with cancer.
CD4 T cell-intrinsic STING signaling controls the differentiation and effector functions of TH1 and TH9 cells
Authors: Benoit-Lizon Isis , Jacquin Elise , Rivera Vargas Thaiz , Richard Corentin , Roussey Aurélie , Dal Zuffo Ludivine , Martin Tiffany , Melis Andréa , Vinokurova Daria , Shahoei Sayyed Hamed , Baeza Garcia Alvaro , Pignol Cassandre , Giorgiutti Stéphane , Carapito Raphaël , Boidot Romain , Végran Frédérique , Flavell Richard A , Ryffel Bernhard , Nelson Eric R , Soulas-Sprauel Pauline , Lawrence Toby , Apetoh Lionel
Published: January 2022

Background

While stimulator of interferon genes (STING) activation in innate immune cells of the tumor microenvironment can result in CD8 T cell-dependent antitumor immunity, whether STING signaling affects CD4 T-cell responses remains elusive.

Methods

Here, we tested whether STING activation modulated the effector functions of CD4 T cells in vivo by analyzing tumor-infiltrating CD4 T cells and evaluating the contribution of the CD4 T cell-derived cytokines in the antitumor activity of the STING ligand 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) in two mouse tumor models. We performed ex vivo experiments to assess the impact of STING activation on CD4 T-cell differentiation and investigate the underlying molecular mechanisms. Finally, we tested whether STING activation enhances TH9 cell antitumor activity against mouse melanoma upon adoptive transfer.

Results

We found that activation of STING signaling cell-intrinsically enhances the differentiation and antitumor functions of TH1 and TH9 cells by increasing their respective production of interferon gamma (IFN-γ) and interleukin-9. IRF3 and type I interferon receptors (IFNARs) are required for the STING-driven enhancement of TH1 cell differentiation. However, STING activation favors TH9 cell differentiation independently of the IFNARs/IRF3 pathway but through mammalian target of rapamycin (mTOR) signaling, underscoring that STING activation differentially affects the fate of distinct CD4 T-cell subsets. The therapeutic effect of STING activation relies on TH1 and TH9-derived cytokines, and STING activation enhances the antitumor activity of TH9 cells upon adoptive transfer.

Conclusion

Our results reveal the STING signaling pathway as a therapeutic target to boost CD4 T-cell effector functions and antitumor immunity.
DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber’s hereditary optic neuropathy and optic atrophy
Authors: Kieninger Sinja , Xiao Ting , Weisschuh Nicole , Kohl Susanne , Rüther Klaus , Kroisel Peter Michael , Brockmann Tobias , Knappe Steffi , Kellner Ulrich , Lagrèze Wolf , Mazzola Pascale , Haack Tobias B , Wissinger Bernd , Tonagel Felix
Published: January 2022

Background

Leber’s hereditary optic neuropathy (LHON) has been considered a prototypical mitochondriopathy and a textbook example for maternal inheritance linked to certain disease-causing variants in the mitochondrial genome. Recently, an autosomal recessive form of LHON (arLHON) has been described, caused by disease-causing variants in the nuclear encoded gene DNAJC30.

Methods and results

In this study, we screened the DNAJC30 gene in a large Central European cohort of patients with a clinical diagnosis of LHON or other autosomal inherited optic atrophies (OA). We identified likely pathogenic variants in 35/1202 patients, corresponding to a detection rate of 2.9%. The previously described missense variant c.152A>G;p.(Tyr51Cys) accounts for 90% of disease-associated alleles in our cohort and we confirmed a strong founder effect. Furthermore, we identified two novel pathogenic variants in DNAJC30: the nonsense variant c.610G>T;p.(Glu204*) and the in-frame deletion c.230_232del;p.(His77del). Clinical investigation of the patients with arLHON revealed a younger age of onset, a more frequent bilateral onset and an increased clinically relevant recovery compared with LHON associated with disease-causing variants in the mitochondrial DNA.

Conclusion

This study expands previous findings on arLHON and emphasises the importance of DNAJC30 in the genetic diagnostics of LHON and OA in European patients.
National evaluation of trauma teaching for students (NETTS)
Authors: Large Jamie , Kumar Prakrit R , Konda Nagarjun N , Hashmi Yousuf , Lee Justine J
Published: January 2022

Despite the shift towards consultant-led care, many patients with trauma are still seen by junior doctors. Previous research has demonstrated that junior doctors feel unprepared to work in acute care but there is a paucity of recent research in trauma specifically. Thus, a national study is required to investigate the current state of undergraduate trauma teaching and identify specific areas for improvement. Between August and September 2020, a 35-item structured questionnaire was distributed among doctors who graduated from UK medical schools within the last 4 years. The questionnaire retrospectively assessed their experience of trauma teaching at medical school and their confidence to diagnose and manage patients with trauma. 398 responses were recorded from graduates of 39 UK medical schools. With 79.6% reporting only 0–5 hours of bedside trauma teaching and 51.8% reporting less than 20 hours in Accident and Emergency, graduates reported that trauma teaching was deficient compared with other specialties (78.1%). The majority of graduates were not confident in the initial assessment (72.9%) of a patient with trauma and almost all felt that a short course in trauma would be useful (93.7%). 77.4% of students felt that online learning would be beneficial and 92.9% felt that simulation would be useful. There is lack of standardised undergraduate trauma teaching nationally; a formal undergraduate teaching to ensure that new graduates are competent in the management of trauma would be supported by students. It is likely that a blended learning approach, incorporating e-learning with traditional teaching and clinical experience would be well received.
Ruled Surfaces of Revolution with Moving Axes and Angles
Authors: Wang Haohao , Goldman Ron
Published: January 2022

A ruled surface of revolution with moving axes and angles is a rational tensor product surface generated from a line and a rational space curve by rotating the line (the directrix) around vectors and angles generated by the rational space curve (the director). Only right circular cylinders and right circular cones are ruled surfaces that are also surfaces of revolution, but we show that a rich collection of other ruled surfaces such as hyperboloids of one sheet, 2-fold Whitney umbrellas, and a wide variety other interesting ruled shapes are ruled surfaces of revolution with moving axes and angles. We present a fast way to compute the implicit equation of a ruled surface of revolution with moving axes and angles from two linearly independent vectors that are perpendicular to the directrix of the surface. We also provide an algorithm for determining whether or not a given rational ruled surface is a ruled surface of revolution with moving axes and angles.
A Survey of Techniques for Fulfilling the Time-Bound Requirements of Time-Sensitive IoT Applications
Authors: Korala Harindu , Georgakopoulos Dimitrios , Jayaraman Prem Prakash , Yavari Ali
Published: January 2022

This article surveys existing techniques for meeting the time-bound requirements of time-sensitive applications in the Internet of Things (IoT). To provide the foundation for identifying and classifying relevant techniques, we present three sample time-sensitive IoT applications and their time-bound requirements, describe the main computation and network resources in IoT that can be used to process such applications, and identify the main challenges in meeting their time-bound requirements. Based on these, the article presents a comprehensive literature review of existing techniques and tools that can help meet application-specific time-bound requirements in IoT. The article also includes a gap analysis in existing research outcomes and proposes research directions for bridging the remaining research gaps in supporting time-sensitive IoT applications.
Pennington Corner: Just Around the Corner
Authors: Calvo Roque J.
Published: January 2022

The “Pennington Corner” was introduced in the first issue of Interface (Winter 1992) to provide information and insights about the Society from the perspective of the Executive Director. Since our headquarters office was located in the center of Pennington at the “corner” of Main Street and Delaware Avenue, the name “Pennington Corner” was a natural for the column. All this is about to change when the Society headquarters office moves to a new location later this year.