bluuebunny/crossref_metadata_2025 huggingface dataset:
A Review of Stress Intensification Factors for Reducers
Authors: Shitolé Bhaskar , Heinrichs Cynthia
Published: November 2023

Determining an accurate stress intensification factor (SIF) is important for piping stress analysis. This paper reviews the history of SIF guidelines for reducers and the significance of reducer geometry on the calculated B31J SIF value.

ASME B31.3 Appendix D, which specifies a SIF of 1 for reducers, was removed in the 2020 version of B31.3 which now references ASME B31J. This means all the process piping stress qualified with SIF = 1 for reducers, may now have stress non-compliance with the new SIF of a value up to 2, resulting in layout or/and material changes in piping systems. This paper reviews the history of the development of SIF for reducers and the effect of this code update on default SIF values for reducers. Next, the significance of different reducer geometry parameters is investigated. In the initial stages of design, details such as exact reducer geometry are often not available. Initial analysis will therefore use default SIF values. These default SIF values should be conservative. If an area is a problem for stress, more detailed information can be used to refine the analysis. SIF values were calculated using default B31J values for reducer alpha, r2, and L2 parameters for a range of ASME B16.9 reducers at two different wall thicknesses. The SIF values are significantly higher than 1 and in many cases reach a value of 2. Most of these geometric parameters such as the L2 distance are not controlled by the ASME B16.9 reducer standard, yet they can have a significant effect on the SIF. It is suggested that L2, the distance between the transition radius and the small end of the reducer, should be specified as L2 >= (D2T2)^0.5 in B16.9 to keep reducer SIF values more predictable.
A Method for Modeling Fluidelastic Instability of Tube Arrays Subjected to Two-Phase Flows
Authors: Farani Sani Hossein , Moran Joaquin , Mohany Atef , Hassan Marwan
Published: November 2023

In this paper, a new model is introduced for predicting the tube response and onset of Fluidelastic Instability (FEI) in tube arrays subjected to two-phase cross-flow. The model is developed based on the methodology proposed by Hassan and Weaver [1] for single-phase flows. The velocity and pressure distribution around the tubes are found using the continuity and momentum equations over a simplified flow channel. The two-phase fluid is modelled by discretizing the flow channel into layers, each having a different void fraction based on the homogeneous equilibrium model. The results obtained agree well with the experimental data available, while the computational cost is significantly reduced when compared to other existing models.
Repair of a Check Valve Seal
Authors: Reich Alton , DiSalvo Roberto
Published: November 2023

Nuclear power supply chains increasingly draw from components that are used in industries with less stringent design and quality requirements. A check valve was selected for a nuclear power application that used a design originally developed for process applications. During post-assembly testing of this valve, it was found to have an unacceptable level of seat leakage. The valve was disassembled, and damage to the valve body and other components was discovered. The root cause was traced to problems during initial assembly that were a direct result of the valve design.

This paper discusses the damage that was found on the valve body, sealing components, seal retaining ring, and draw plate. The manufacturing issues that contributed to the sealing failure are also discussed. The valve sealing mechanism was redesigned in order to correct the problem and repair the already manufactured valves. Several options were considered for repairing the valves and correcting the manufacturing and design defects. Each of these options had disadvantages, and the relative strengths and weaknesses of each option are considered. The selected repair method was qualified using Code rules and the repaired valves were tested to ensure that they met the design requirements. Finally, we discuss lessons learned that can be applied to future valve designs and efforts to utilize equipment originally designed for other industries in nuclear power applications.
Stress Analysis and Backfilling Measures of Gas Pipeline Buried in Embankment of Tunnel
Authors: Wu Jia , Xia Li , Tang Ping
Published: November 2023

Long distance pipelines are usually laid in tunnels to overcome the complexity of geological environment and reduce the construction and maintenance costs. However, pipelines in tunnels may fail for many reasons. Therefore, in order to reduce potential safety hazards and improve the reliability of pipelines, it is necessary to conduct stress analysis on pipelines crossing tunnels. In a project, the gas transmission pipeline in a tunnel is buried in embankment. Considering the surrounding actual conditions, pipeline operation status and other factors, it is necessary to formulate the pipeline backfilling plan and evaluate its stress level. To solve this problem, this paper uses finite element software to establish the pipeline model, and analyzes the stress and displacement under different conditions. The influence of buried depth and overburden compaction multiplier on stress and displacement is also studied. Through the above simulation, the distribution law of stress and displacement is obtained, and the reasonable buried depth and overburden compaction multiplier are found. Then, according to the simulation results, appropriate backfilling measures are taken to ensures the construction of the project and the safe operation of the pipeline.
Seal Failure Analysis of O-Ring Seal Based on Two-Way Fluid-Structure Interaction
Authors: Ma Xinao , Li Qingye , Zong Chaoyong , Zhou Weihao , Song Xueguan
Published: November 2023

O-ring seal is widely used in pressure system to prevent leakage of the fluid medium. However, in actual situations, excessive pressure of the system and the unreasonable structure usually led to the severe distortion of the O-ring seal, which may result in the seal failure and thus medium leakage. To explore the mechanism of these failures, a two-way fluid-structure interaction (FSI) based analysis was carried out in this paper, where the model of O-ring seal is constructed based on the Mooney-Rivlin hyperplastic constitutive model and the dynamic mesh technique. Through simulations, the stress distribution and the deformation of the O-ring seal under 100 MPa pressure conditions were predicted, verifying the ability of the developed numerical model. On this basis, both one-way and two-way FSI simulations were performed, and the pressure ratio of the sealing surface were compared, which indicates that there is obvious difference between these two types of simulations, the pressure ratio produced by the one-way simulations were higher than that obtained from two-way FSI simulations. Since the two-way FSI takes the sealing surface changing into consideration, to ensure the accuracy, it was used in the follow-up analysis works. By observing the simulated strain and stress distribution, it is determined that seal surface near the two right angles of the limiting plate is the key part prone to medium leakage, which provides a basis for the structural optimization design of the O-ring seal.
Research on Optimization of Database Security System of Chemical Industry Park Structures
Authors: Cao Yuxuan , Liu Kejing , Xue Rui , Xu Kaijian , Fang Zhou
Published: November 2023

As an important part of building safety, the safety of chemical industry park structures is of great significance to the improvement and development of the global security system. However, there are still some problems in the design and use of the safety database of chemical structures, such as incomplete information of structures and materials, low integrity of data information, and poor systematic Ness. In this paper, a new database is designed to solve the problems existing in the current chemical industry park structure database. First, establish a new type of database to sort out and store information, including three modules: building information, environment and personnel information, and accident management information. Secondly, through the existing calculation and analysis methods, carry out data analysis for the organic coupling of different modules, and for the possible safety accidents of chemical structures, realize the main functions of optimizing design and construction, assisting daily maintenance, and improving rescue efficiency, Finally, the optimal selection or design measures are provided according to the analysis results, and the final scheme is given according to the specific requirements of the country. In addition, the new database can improve the efficiency of the government’s integrated management of chemical structures and provide data support for improving the building safety system.
Simulation of PA-UT Sector Scanning Imaging of Irregular Defects in Polyethylene Pipe Based on Finite Element Analysis
Authors: Chen Zhuoyu , Feng Ying , Tao Yangji , Wang Zhongzhen , Shi Jianfeng
Published: November 2023

Phased array ultrasonic testing (PA-UT) is a common nondestructive testing technology for polyethylene pipelines. However, the images of PA-UT results may distort due to the acoustic focusing and image construction laws of the inspecting system, especially when performing sector scanning inspection, in which the emitting acoustic waves are more challenging to be converged at the focus points. Therefore, exploring an image reconstructing method is necessary to reduce or eliminate the image distortion of PA-UT results. In practice, more than the number and richness of defect image samples detected by PA-UT is needed to support the research of defect reconstruction. In this paper, based on finite element simulation of the phased array inspecting process, sector scanning simulations of defects of different dimensions and positions were carried out, and the results were obtained based on acoustic focusing and image construction laws. Meanwhile, testing blocks containing the same artificial defects were made and inspected using PA-UT. By comparing the experimental results and finite element simulation, it was found that the simulation models can simulate the distortion features in the results of the sector scanning. Based on the verified model, the imaging features of irregular defects with different dimensions and positions were analyzed, and the regulations of distortion during PA-UT inspecting were preliminarily summarized.
Review on Hydrogen-Induced Failure of Rubber O-Rings for High Pressure Hydrogen Storage Tanks
Authors: Chen Qi , Yang Miaomiao , Peng Wenzhu , Yao Riwu , Shi Jianfeng
Published: November 2023

The hydrogen is prone to leakage, and the explosion risk after hydrogen leakage is high due to the low ignition temperature and large combustion and explosion range (4%–74%). Therefore, the sealing of high pressure hydrogen storage vessels is crucial for the safe use of hydrogen. Rubber O-rings are common sealing element in high pressure hydrogen storage tanks. High pressure hydrogen storage tanks are subjected to severe conditions such as high and low temperature, heat shock, high pressure and pressure cycle, resulting in extrusion fracture, bending fracture, blister fracture and increase of compression set of rubber O-rings during the service. This paper introduces the materials, application and performance requirements of rubber O-rings, and discussed hydrogen-induced damages and failure modes of rubber O-rings. The research progress of hydrogen-induced failure was then reviewed from aspects of experimental studies and finite elements analysis. The functions and experimental parameters of the current experimental devices for hydrogen-induced damage of rubber O-rings were comprehensively introduced, and the difference between the experimental conditions and the actual service conditions were compared and analyzed. It was concluded that the damage evolution mechanism of rubber O-rings under the coupling of temperature, pressure and hydrogen during high pressure hydrogen cycle was not fully understood, especially in the scenario of rapid hydrogen charging and discharging. Finally, it provides research ideas for future work.
Design Data for Alloy 740H High Temperature Concentrating Solar Power Components
Authors: Barua B. , Messner M. C. , Bass R. E. , McMurtrey M. D.
Published: November 2023

Recently, Barua et. al [ANL-20/03, 2020] developed new design rules for high temperature concentrating solar power metallic components. These rules are to be used in conjunction with the Section III, Division 5 rules of the ASME Boiler & Pressure Vessel Code and include three design by analysis options — i) design by elastic analysis with reduced margin, ii) design by elastic analysis with reduced margin and simplified creep-fatigue evaluation, and iii) design by inelastic analysis. In this paper, we report the corresponding design data for a nickelbased high temperature alloy – Alloy 740H. The current Alloy 740H Code Case includes some basic material properties such as Young’s modulus, Poisson’s ratio, thermal properties, yield strength, tensile strength, and allowable stress So. However, a complete design check for high temperature components — i.e., primary load and buckling checks, ratcheting strain limits, and creep-fatigue evaluation — requires additional material data including allowable stress Sm, relaxation strength, isochronous stress-strain curves, minimum-stress-to-rupture Sr, fatigue diagrams, and creep-fatigue damage envelope. We construct these design data from the available material data in the literature and data generated recently at Idaho National Laboratory as part of a U.S. Department of Energy – Solar Energy Technology Office funded project. We also develop an inelastic constitutive model for use with the design by inelastic analysis method.
Numerical Modeling of Strain Rate Effects on the Post Expansion Properties of Expandable Tubular
Authors: Alrasheedi Nashmi , Khan Rashid , Pervez Tasneem , Qamar Syed Zahid , Akhtar Maaz , Arsalan Muhammad
Published: November 2023

The paper presents numerical modeling of tubular expansion for predicting the strain rate effects on post expansion tubular properties. The down-hole expandable tubular has proven itself to be a vital technology in oil well applications. However, there are several challenges faced by researchers and field engineers in implementing and making the technology cost effective while conserving the structural integrity of tubular in post expansion applications. The cold expansion greatly affects the mechanical properties and induces residual stresses in the tubular, which may harm the collapse, burst, and fatigue ratings. Hence, a comprehensive knowledge of tubular’s properties variation is needed in correctly predicting the life span under given operational conditions. Moreover, the expansion rate of full length (3–4 m ∼ 10–13 ft) tubular is also a prime parameter at the field to control the cost of expansion. As required, the rate of expansion must be as high as possible. However, this may greatly affect the material and geometrical properties. Therefore, an exhaustive analysis is required to investigate the effects of strain rate on post expansion tubular properties. In the current work, numerical model is developed of tubular-mandrel system by considering the Johnson-Cook strain rate dependent material model of tubular. The hardening parameters of this are obtained through regression analysis of the uniaxial tensile test data of standard specimen of tubular material. The tension tests are performed at different strain rates vary from 0.05 s−1 to 0.3 s−1. In numerical simulations, the rate of expansion varies by changing the velocity of mandrel from 5 mm/s to 25 mm/s or 5 in/s – 1 in/s. The numerical results are validated and found to be in good agreement with the experimental observations. Finally, further simulations are executed to estimate the variation of contact pressure at tubular-mandrel interface, effective stress, equivalent plastic strain, thickness reduction, and length shortening during expansion process.
Assessment of Fatigue Using Elastic-Plastic Analysis in ASME Section III Appendix XIII: A Proposed Approach and Technical Justification
Authors: Damiani Thomas M. , Matusin Cory S.
Published: November 2023

With ever-increasing computing speed and the enhanced capabilities of commercial finite element analysis software, the use of Elastic-Plastic methods within the ASME Boiler and Pressure Vessel Code has become more widely used for design analysis and fitness-for-service evaluations. The rules in Section III, Appendix XIII, and NB-3200 for pre-2018 versions of the Code, pertaining to the use of “Plastic Analysis” to satisfy the allowable limits for fatigue have been under development in the Section III Working Group on Fatigue Strength. Drawing from methods that are established within ASME Section III Division 5 and Section VIII Division 2, proposed revisions to various sections of Appendix XIII to integrate the use of Plastic Analysis methods into the rules in Section XIII-3440 and -3520 of Appendix XIII are outlined and explained. Additionally, definitions for the calculation of a corollary to the alternating stress amplitude (Salt), referred to as the alternating strain amplitude (εalt), for use in conjunction with the design fatigue curves to calculate a fatigue cumulative usage factor (CUF) are developed. As part of this effort there was an international round robin to evaluate various strain measures and analysis methods, the details of which are documented in a companion paper within this conference. The purpose of this paper is to summarize the proposed changes stemming from the code work and the round robin, and to present the technical justification for use in the balloting process.
Case Study: Transient Thermal Analysis of Valve Flanges
Authors: Seipp Trevor G. , Gu Ming (Forrest) , Brown Robert , Chatham Everett
Published: November 2023

Isolation valves were planned for installation in a vacuum distillation unit heater outlet piping that connects the vacuum transfer line to the vacuum column. These valves had a modified ASME B16.47 Series A, NPS 32, Class 300 flange that mated to a standard ASME B16.47 Series A, NPS 32, Class 300 flange. Previous experience in this service had shown that the thermal transients experienced during start-up and shutdown could cause leakage of the flanges.

While there are a number of different parameters that can impact the performance of a bolted flange joint during transient thermal conditions, such as gasket type, gasket width, gasket OD, gasket thickness, and assembly bolt loads, this paper exclusively examines the effects of the assembly bolt loads. Thermal finite element analyses were performed to simulate the thermal transient events. Sequentially-coupled mechanical analyses were performed examining the above-noted parameters. The analyses were performed using a 2D-axisymmetric approach, and validated by a 3D-solid model. The leak-tightness of the various configurations were assessed by calculating the compressive stresses in the gasket across the full gasket width and comparing to an optimal gasket operating stress. The sealing face flatness was assessed after several simulated cycles to determine if any permanent deformation occurs in the flange face.

Three flange configurations were evaluated in this case study: the downstream flange pair, the upstream flange pair, including a spacer ring/spectacle blind, and a regular weld neck-to-weld neck flange.

This paper presents the results of the case study and demonstrates several techniques for evaluating bolted flange joints and their critical parameters.
KDM6B drives epigenetic reprogramming associated with lymphoid stromal cell early commitment and immune properties
Authors: Sylvestre Marvin , Barbier Nicolas , Sibut Vonick , Nayar Saba , Monvoisin Céline , Leonard Simon , Saint-Vanne Julien , Martin Ansie , Guirriec Marion , Latour Maëlle , Jouan Florence , Baulande Sylvain , Bohec Mylène , Verdière Léa , Mechta-Grigoriou Fatima , Mourcin Frédéric , Bertheuil Nicolas , Barone Francesca , Tarte Karin , Roulois David
Published: November 2023

Mature lymphoid stromal cells (LSCs) are key organizers of immune responses within secondary lymphoid organs. Similarly, inflammation-driven tertiary lymphoid structures depend on immunofibroblasts producing lymphoid cytokines and chemokines. Recent studies have explored the origin and heterogeneity of LSC/immunofibroblasts, yet the molecular and epigenetic mechanisms involved in their commitment are still unknown. This study explored the transcriptomic and epigenetic reprogramming underlying LSC/immunofibroblast commitment. We identified the induction of lysine demethylase 6B (KDM6B) as the primary epigenetic driver of early immunofibroblast differentiation. In addition, we observed an enrichment for KDM6B gene signature in murine inflammatory fibroblasts and pathogenic stroma of patients with autoimmune diseases. Last, KDM6B was required for the acquisition of LSC/immunofibroblast functional properties, including the up-regulation of CCL2 and the resulting recruitment of monocytes. Overall, our results reveal epigenetic mechanisms that participate in the early commitment and immune properties of immunofibroblasts and support the use of epigenetic modifiers as fibroblast-targeting strategies in chronic inflammation.
Manipulating the growth environment through co-culture to enhance stress tolerance and viability of probiotic strains in the gastrointestinal tract
Authors: Oana Kosuke , Shimizu Kensuke , Takada Toshihiko , Makino Hiroshi , Yamazaki Mikiko , Katto Miyuki , Ando Minoru , Kurakawa Takashi , Oishi Kenji
Published: November 2023

The viability of probiotics in the gastrointestinal tract is essential because it has an important role in their health benefits. Plasticity is a phenomenon associated with stress tolerance in bacteria, and stress tolerance of probiotic strains can be induced by the use of additives and weak stress. However, some of these processes are difficult to implement in the manufacture of probiotic beverages, and there are few methods that can be easily applied. Co-culture techniques have been used to produce fermented beverages and may impart distinct characteristics through differences in the culture environment compared with those of monoculture. Here, we show that the stress tolerance of a probiotic strain was altered by co-culture with other strains already used in product manufacturing. Stress tolerance in
Lacticaseibacillus paracasei
strain Shirota was enhanced by co-culture with
Lactococcus lactis
subsp.
lactis
YIT 2027 as a result of an earlier pH decrease. Therefore, the stress tolerance was similarly improved in monocultures where pH was manipulated. Strains with improved stress tolerance had an increase in dihydrosterculic acid in the cell membrane, with altered gene transcription in energy metabolism, lipid metabolism, and chaperone genes. Moreover, fermented beverage consumption studies revealed that the probiotics produced through co-culture were significantly more viable in the human gastrointestinal tract than those produced through monoculture. These data suggested that co-culture with specific strains can significantly enhance the viability of probiotic strains in the human gastrointestinal tract.

IMPORTANCE

The viability of probiotics in the human gastrointestinal tract is important, as some reports indicate that the health benefits of live bacteria are greater than those of dead ones. Therefore, the higher the viability of the probiotic strain, the better it may be. However, probiotic strains lose their viability due to gastrointestinal stress such as gastric acid and bile. This study provides an example of the use of co-culture or pH-controlled monoculture, which uses more stringent conditions (lower pH) than normal monoculture to produce probiotic strains that are more resistant to gastrointestinal stress. In addition, co-cultured beverages showed higher viability of the probiotic strain in the human gastrointestinal tract than monocultured beverages in our human study.
Circular genomes of two bacterial strains capable of growing in a CO
2
-containing atmosphere
Authors: Heidler von Heilborn David , Bartholomäus Alexander , Lipski André
Published: November 2023

The bacterial strains
Brochothrix thermosphacta
DH-B18 and
Rathayibacter
sp. DH-RSZ4 were isolated from raw sausage and escalope samples and grown in a CO
2
-rich modified atmosphere. Here, we present both circular genomes obtained by nanopore sequencing.
A transcriptomic atlas of acute stress response to low pH in multiple
Issatchenkia orientalis
strains
Authors: Dubinkina Veronika , Bhogale Shounak , Hsieh Ping-Hung , Dibaeinia Payam , Nambiar Ananthan , Maslov Sergei , Yoshikuni Yasuo , Sinha Saurabh
Published: November 2023

Because of its natural stress tolerance to low pH,
Issatchenkia orientalis (a.k.a. Pichia kudriavzevii)
is a promising non-model yeast for bio-based production of organic acids. Yet, this organism is relatively unstudied, and specific mechanisms of its tolerance to low pH are poorly understood, limiting commercial use. In this study, we selected 12
I. orientalis
strains with varying acid stress tolerance (six tolerant and six susceptible) and profiled their transcriptomes in different pH conditions to study potential mechanisms of pH tolerance in this species. We identified hundreds of genes whose expression response is shared by tolerant strains but not by susceptible strains, or vice versa, as well as genes whose responses are reversed between tolerant and susceptible strains. We mapped regulatory mechanisms of transcriptomic responses via motif analysis as well as differential network reconstruction, identifying several transcription factors, including Stb5, Mac1, and Rtg1/Rtg3, some of which are known for their roles in acid response in
Saccharomyces cerevisiae
. Functional genomics analysis of short-listed genes and transcription factors suggested significant roles for energy metabolism and translation-related processes, as well as the cell wall integrity pathway and RTG-dependent retrograde signaling pathway. Finally, we conducted additional experiments for two organic acids, 3-hydroxypropionate and citramalate, to eliminate acid-specific effects and found potential roles for glycolysis and trehalose biosynthesis specifically for response to low pH. In summary, our approach of comparative transcriptomics and phenotypic contrasting, along with a multi-pronged bioinformatics analysis, suggests specific mechanisms of tolerance to low pH in
I. orientalis
that merit further validation through experimental perturbation and engineering.

IMPORTANCE

Issatchenkia orientalis
is a promising industrial chassis to produce biofuels and bioproducts due to its high tolerance to multiple environmental stresses such as low pH, heat, and other chemicals otherwise toxic for the most widely used microbes. Yet, little is known about specific mechanisms of such tolerance in this organism, hindering our ability to engineer this species to produce valuable biochemicals. Here, we report a comprehensive study of the mechanisms of acidic tolerance in this species via transcriptome profiling across variable pH for 12 different strains with different phenotypes. We found multiple regulatory mechanisms involved in tolerance to low pH in different strains of
I. orientalis
, marking potential targets for future gene editing and perturbation experiments.
Quercetin targets SarA of methicillin-resistant
Staphylococcus aureus
to mitigate biofilm formation
Authors: Liu Panpan , Kang Xinyun , Chen Xiaohui , Luo Xiaofeng , Li Caixia , Wang Guiqin
Published: November 2023

The emergence of methicillin-resistant
Staphylococcus aureus
(MRSA) led to the failure of conventional antibiotic treatment, resulting in serious morbidity and mortality. The biofilm formation of
S. aureus
is a potential mechanism for drug resistance. SarA is an important regulatory protein for the formation of
S. aureus
biofilm. In this study, the global regulator SarA was used as a target to virtually screen natural active monomers. SarA inhibitor quercetin (QEN) was assessed. Molecular docking and kinetic simulation showed that QEN was stably bound to the formation site of SarA dimer. Spectral analysis verified that QEN was bound to SarA and changed its conformation.
In vitro
biofilm, the culture showed that 4 µg/mL QEN significantly inhibited biofilm formation, and the production of extracellular polymers and eDNA concentration significantly reduced. Scanning electron microscopy and laser confocal microscopy further confirmed the inhibitory effect of QEN on biofilm formation. At the same time, a decrease in the transcription level of
sarA
and its downstream genes related to biofilm regulation and a decrease in the expression level of SarA were also observed, confirming the QEN-induced inhibition of
sarA
. In conclusion, the results of this study revealed SarA-mediated anti-biofilm effect of QEN on MRSA.

IMPORTANCE

Anti-biofilm is an important strategy against
Staphylococcus aureus
chronic infection. SarA is a positive regulator of biofilm formation in
S. aureus
. In this study, we identified the SarA inhibitor quercetin using computer simulation screening. Previous studies have shown that quercetin inhibits biofilm; however, the underlying mechanism remains unknown. This study revealed the inhibitory effect of quercetin on the SarA protein. We also isolated the SarA protein and confirmed its interaction with quercetin
in vitro
. Besides, the inhibitory effect of quercetin on the transcription and translation levels of the SarA protein was also determined. The effects of quercetin on
S. aureus
biofilm inhibition and biofilm components were consistent with the changes in the transcription level of biofilm-related genes regulated by SarA. In summary, our study revealed the mechanism by which quercetin affects biofilm formation by inhibiting the transcriptional regulator SarA of
S. aureus
.
Zika virus infection triggers caspase cleavage of STAT1
Authors: Shu Jun , Ma Xiao , Zou Jingyi , Yuan Zhenghong , Yi Zhigang
Published: November 2023

Zika virus (ZIKV) is an important pathogen that causes Guillain-Barre syndrome in adults and congenital Zika syndrome in newborns. Interferon (IFN) triggers intracellular antiviral signaling through two essential mediators STAT1 and STAT2, which are critical for host innate antiviral immunity. ZIKV has been reported to antagonize host IFN signaling by diverse mechanisms, including NS5-dependent and -independent ablation of STAT2. Whether flaviviruses target STAT1 remains controversial. In this study, we used infectious clones of ZIKV MR766 as tools and found that ZIKV infection triggered caspase-dependent cleavage of STAT1 during late infection. Further studies identified that the cleavage site is the aspartic acid 694, and the D694A mutation rendered STAT1 resistant to ZIKV infection-induced cleavage. Murine STAT1 (mSTAT1) was resistant to cleavage in ZIKV-infected cells. Ectopically expressed STAT1.D694A and mSTAT1 exerted comparable anti-ZIKV activity upon IFN treatment, challenging the role of STAT1 cleavage in IFN antagonism. We further knocked out STAT1 in the mouse embryonic fibroblast NIH3T3 cells, and STAT1 knockout dramatically augmented ZIKV infection, suggesting a STAT1-mediated viral restriction. Intriguingly, in the STAT1-knockout NIH3T3 cells, complementation of mSTAT1.D695G, a cleavage-sensitive variant, and the wild-type mSTAT1 both restored comparable anti-viral activities. These data suggest that caspase-mediated STAT1 cleavage is dispensable for IFN antagonism in ZIKV-infected cells.

IMPORTANCE

Zika virus (ZIKV) is a re-emerging flavivirus. Similar to other flaviviruses, ZIKV antagonizes the host interferon (IFN) signaling pathway to establish infection. Understanding the molecular mechanism by which ZIKV antagonizes IFN-induced antiviral signaling may lead to a new antiviral strategy by cracking the IFN antagonism. Flaviviruses have been reported to employ NS5-dependent and -independent mechanisms to block STAT2-mediated signaling, whereas whether flaviviruses target STAT1 remains controversial. Herein, we found that ZIKV infection triggered caspase-dependent cleavage of STAT1 at the aspartic acid 694 during late infection, whereas murine STAT1 (mSTAT1) was resistant to cleavage. Intriguingly, ectopically expressed cleavage-resistant human STAT1.D694A or complementation of cleavable mSTAT1.D695G exerted comparable anti-ZIKV activity with their counterparts, challenging the role of caspase-mediated STAT1 cleavage in the IFN antagonism in ZIKV-infected cells. These data may also imply a dominant role of the antagonism of STAT2 but not STAT1 in ZIKV-infected cells.
Fifteen-minute consultation: Management of albuminuria in children and young people with diabetes
Authors: Weber Isabella , Myles Cliodhna , Hendriks A Emile J , Marcovecchio M Loredana , Fisher Benjamin G
Published: November 2023

Albuminuria is a marker of diabetic kidney disease. Raised albuminuria in children and young people with diabetes is associated with an increased risk of microvascular and macrovascular complications. This review provides guidance for paediatricians caring for children and young people with type 1 and type 2 diabetes on screening, investigations and treatments for albuminuria in line with relevant national and international recommendations.
Association between leisure sedentary behaviour and uterine fibroids in non-menopausal women: a population-based study
Authors: Sun Yunrui , Han Xiaoyu , Hou Zhongxin , Deng Haoyuan , Cheng Nan , Zhang Nishang , Zhang Jianghui , Li Yi , Wang Qian , Yin Jianzhong , Meng Qiong
Published: November 2023

Objective

Sedentary behaviour is associated with a variety of adverse health outcomes, including obesity, oestrogen metabolism and chronic inflammation, all of which are related to the pathogenesis of uterine fibroids (UFs). This study aimed to explore the relationship between leisure sedentary time (LST) and UFs.

Design

Cross-sectional.

Setting

We conducted a cross-sectional analysis of data from patients from the Yunnan region in the China Multi-Ethnic Cohort Study.

Participants

A total of 6623 non-menopausal women aged 30–55 years old were recruited. Menstrual status was self-reported. Participants who lacked a unique national identity card, suffered from serious mental illness, did not have a clear diagnosis of UFs, or provided incomplete information were excluded.

Primary and secondary outcome

UFs were diagnosed by abdominal B-ultrasound. Leisure sedentary behaviour was assessed by using a face-to-face questionnaire interview. Logistic regression and restricted cubic spline were employed to explore the relationship between LST and UFs.

Results

A total of 562 participants had UFs, with a prevalence rate of 8.5% (7.8%, 9.2%). Multivariate adjusted logistic regression analysis showed that the risk of UFs in women with LST≥6 hour/day was 2.008 times that in women with LST<2 hour/day (95% CI 1.230 to 3.279). The restricted cubic spline results showed that there was a linear dose‒response relationship between LST and UFs (p for non-linearity>0.05). According to the results of the stratified analysis for menstrual status and body mass index (BMI), there was a correlation between LST and the prevalence of UFs only in women with a BMI<24 kg/m2or perimenopause.

Conclusion

LST was independently associated with the prevalence of UFs, and a linear dose‒response relationship was observed. Our study provides evidence on the factors influencing UFs, and further research is needed to propose feasible measures for UFs prevention.
Patient safety in remote primary care encounters: multimethod qualitative study combining Safety I and Safety II analysis
Authors: Payne Rebecca , Clarke Aileen , Swann Nadia , van Dael Jackie , Brenman Natassia , Rosen Rebecca , Mackridge Adam , Moore Lucy , Kalin Asli , Ladds Emma , Hemmings Nina , Rybczynska-Bunt Sarah , Faulkner Stuart , Hanson Isabel , Spitters Sophie , Wieringa Sietse , Dakin Francesca H , Shaw Sara E , Wherton Joseph , Byng Richard , Husain Laiba , Greenhalgh Trisha
Published: November 2023

Background

Triage and clinical consultations increasingly occur remotely. We aimed to learn why safety incidents occur in remote encounters and how to prevent them.

Setting and sample

UK primary care. 95 safety incidents (complaints, settled indemnity claims and reports) involving remote interactions. Separately, 12 general practices followed 2021–2023.

Methods

Multimethod qualitative study. We explored causes of real safety incidents retrospectively (‘Safety I’ analysis). In a prospective longitudinal study, we used interviews and ethnographic observation to produce individual, organisational and system-level explanations for why safety and near-miss incidents (rarely) occurred and why they did not occur more often (‘Safety II’ analysis). Data were analysed thematically. An interpretive synthesis of why safety incidents occur, and why they do not occur more often, was refined following member checking with safety experts and lived experience experts.

Results

Safety incidents were characterised by inappropriate modality, poor rapport building, inadequate information gathering, limited clinical assessment, inappropriate pathway (eg, wrong algorithm) and inadequate attention to social circumstances. These resulted in missed, inaccurate or delayed diagnoses, underestimation of severity or urgency, delayed referral, incorrect or delayed treatment, poor safety netting and inadequate follow-up. Patients with complex pre-existing conditions, cardiac or abdominal emergencies, vague or generalised symptoms, safeguarding issues, failure to respond to previous treatment or difficulty communicating seemed especially vulnerable. General practices were facing resource constraints, understaffing and high demand. Triage and care pathways were complex, hard to navigate and involved multiple staff. In this context, patient safety often depended on individual staff taking initiative, speaking up or personalising solutions.

Conclusion

While safety incidents are extremely rare in remote primary care, deaths and serious harms have resulted. We offer suggestions for patient, staff and system-level mitigations.
Health services under pressure: a scoping review and development of a taxonomy of adaptive strategies
Authors: Page Bethan , Irving Dulcie , Amalberti Rene , Vincent Charles
Published: November 2023

Objective

The objective of this review was to develop a taxonomy of pressures experienced by health services and an accompanying taxonomy of strategies for adapting in response to these pressures. The taxonomies were developed from a review of observational studies directly assessing care delivered in a variety of clinical environments.

Design

In the first phase, a scoping review of the relevant literature was conducted. In the second phase, pressures and strategies were systematically coded from the included papers, and categorised.

Data sources

Electronic databases (MEDLINE, Embase, CINAHL, PsycInfo and Scopus) and reference lists from recent reviews of the resilient healthcare literature.

Eligibility criteria

Studies were included from the resilient healthcare literature, which used descriptive methodologies to directly assess a clinical environment. The studies were required to contain strategies for managing under pressure.

Results

5402 potential articles were identified with 17 papers meeting the inclusion criteria. The principal source of pressure described in the studies was the demand for care exceeding capacity (ie, the resources available), which in turn led to difficult working conditions and problems with system functioning. Strategies for responding to pressures were categorised into anticipatory and on-the-day adaptations. Anticipatory strategies included strategies for increasing resources, controlling demand and plans for managing the workload (efficiency strategies, forward planning, monitoring and co-ordination strategies and staff support initiatives). On-the-day adaptations were categorised into: flexing the use of existing resources, prioritising demand and adapting ways of working (leadership, teamwork and communication strategies).

Conclusions

The review has culminated in an empirically based taxonomy of pressures and an accompanying taxonomy of strategies for adapting in response to these pressures. The taxonomies could help clinicians and managers to optimise how they respond to pressures and may be used as the basis for training programmes and future research evaluating the impact of different strategies.
‘The dark before the dawn’: the 2021 British Thoracic Society Audit of the treatment of tobacco dependency in acute trusts
Authors: Devani Nikesh , Mangera Zaheer , Smith Howard , Gates Jessica , Woodhouse Arran , Fullerton Duncan , Ponnuswamy Aravind , Evison Matthew
Published: November 2023

Smoking remains the single largest cause of preventable death, disability and health inequality. Smoking tobacco directly contributes to over 500 000 hospital admissions each year, making hospitals an important location to optimise treatment for tobacco dependency. The third British Thoracic Society Tobacco Dependency Audit was undertaken to determine how effectively national standards for treating tobacco-dependent smokers have been implemented and assess if any progress has been made from previous audits. Data on 14579 patients from 119 hospitals revealed 21% of patients were current smokers, 45% were offered very brief advice and 5% prescribed combination nicotine replacement therapy or varenicline. Only 9% completed a consultation with a specialist tobacco dependency practitioner during their inpatient stay and fewer than 1% of smokers were abstinent at 4 weeks following discharge. Clinical leadership of tobacco dependency services was deficient, and staff were ill equipped in supporting current smokers in their efforts to quit with only 50% of trusts offering regular smoking cessation training. There has been little meaningful improvement from previous audits and there remains woefully inadequate provision of tobacco dependency treatment for patients who smoke. The National Health Service (NHS) Long Term Plan has committed substantial, new funding to the NHS to ensure every patient that smokes admitted to hospital will be offered evidence-based support and treatment for tobacco dependency. The findings of this audit highlight the urgency with which this programme must be implemented to tackle the greatest cause of premature death in the UK and to achieve the wider well-recognised benefits for the healthcare system.
Delayed vaccine-induced CD8+T cell expansion by topoisomerase I inhibition mediates enhanced CD70-dependent tumor eradication
Authors: van der Sluis Tetje C , van Haften Floortje J , van Duikeren Suzanne , Pardieck Iris N , de Graaf J Fréderique , Vleeshouwers Ward , van der Maaden Koen , Melief Cornelis J M , van der Burg Sjoerd H , Arens Ramon
Published: November 2023

Background

The survival of patients with cervical cancer who are treated with cisplatin in conjunction with the topoisomerase I inhibitor topotecan is enhanced when compared with patients treated with only one of these chemotherapeutics. Moreover, cisplatin-based and T cell-based immunotherapy have been shown to synergize, resulting in stronger antitumor responses. Here, we interrogated whether topotecan could further enhance the synergy of cisplatin with T cell-based cancer immunotherapy.

Methods

Mice bearing human papilloma virus 16 (HPV16) E6/E7-expressing TC-1 tumors were vaccinated with HPV16 E7 long peptides and additionally received chemotherapy consisting of cisplatin and topotecan. We performed an in-depth study of this combinatorial chemoimmunotherapy on the effector function and expansion/contraction kinetics of vaccine-induced CD8+T cells in the peripheral blood and tumor microenvironment (TME). In addition, we interrogated the particular role of chemotherapy-induced upregulation of costimulatory ligands by tumor-infiltrated myeloid cells on T cell proliferation and survival.

Results

We show that E7 long peptide vaccination combined with cisplatin and topotecan, results in CD8+T cell-dependent durable rejection of established tumors and 94% long-term survival. Although topotecan initially repressed the expansion of vaccine-induced CD8+T cells, these cells eventually expanded vigorously, which was followed by delayed contraction. These effects associated with the induction of the proliferation marker Ki-67 and the antiapoptosis molecule Bcl-2 by intratumoral tumor-specific CD8+T cells, which was regulated by topotecan-mediated upregulation of the costimulatory ligand CD70 on myeloid cells in the TME.

Conclusions

Taken together, our data show that although treatment with cisplatin, topotecan and vaccination initially delays T cell expansion, this combinatorial therapy results eventually in a more robust T cell-mediated tumor eradication due to enhancement of costimulatory molecules in the TME.
Supportive relationships between patients and family caregivers in specialist palliative care: a qualitative study of barriers and facilitators
Authors: McCauley Rachel , Ryan Karen , McQuillan Regina , Selman Lucy E , Foley Geraldine
Published: November 2023

Objectives

Patients with advanced illness and their family caregivers can be mutually supportive. However, what facilitates and/or restricts supportive relationships between patients and family caregivers in palliative care remains unclear. We aimed to identify key barriers to and facilitators of supportive relationships between people with advanced illness and family caregivers in specialist palliative care.

Methods

A qualitative study using grounded theory methodology was conducted. Semistructured interviews were undertaken with 15 patients with advanced illness and 21 family caregivers purposively and theoretically sampled from a large regional specialist palliative care service. Verbatim transcripts were analysed in line with grounded theory coding procedures.

Results

Mutual support was underpinned by mutual concern and understanding. Facilitators of supportive relationships included patients and family caregivers already having a close relationship, caregivers assuming caregiving duties by choice, caregivers feeling competent in a caregiving role, patients valuing caregiver efforts, availability of respite for the caregiver and direct support from healthcare professionals to help both patients and caregivers adjust to advanced illness. Barriers to supportive relationships included absence of support from the wider family, prior mutual conflict between the patient and caregiver, caregivers feeling constrained in their caregiving role and patient and caregiver distress induced by mutual loss.

Conclusions

Multiple factors at both a micro (eg, relationship based) and mesolevel (eg, assistance from services) impact patient and family caregiver ability to support one another in specialist palliative care. Supportive relationships between patients and family caregivers are mediated by feelings pertaining to both control and loss.